WO2005086638A2 - Analogues inhibiteurs de la proliferation cellulaire, leurs procedes de fabrication, et leurs utilisations - Google Patents

Analogues inhibiteurs de la proliferation cellulaire, leurs procedes de fabrication, et leurs utilisations Download PDF

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Publication number
WO2005086638A2
WO2005086638A2 PCT/US2005/004759 US2005004759W WO2005086638A2 WO 2005086638 A2 WO2005086638 A2 WO 2005086638A2 US 2005004759 W US2005004759 W US 2005004759W WO 2005086638 A2 WO2005086638 A2 WO 2005086638A2
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hydrocarbon
saturated
unsaturated
aliphatic
heterocycle
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PCT/US2005/004759
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English (en)
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WO2005086638A3 (fr
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Duane D. Miller
James T. Dalton
Veeresa Gududuru
Eunju Hurh
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The Ohio State University Research Foundation
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Priority to EA200601471A priority Critical patent/EA200601471A1/ru
Priority to AU2005220705A priority patent/AU2005220705A1/en
Priority to JP2006553347A priority patent/JP2007522247A/ja
Priority to BRPI0507612-9A priority patent/BRPI0507612A/pt
Priority to EP05749117A priority patent/EP1723127A4/fr
Priority to CA002559333A priority patent/CA2559333A1/fr
Publication of WO2005086638A2 publication Critical patent/WO2005086638A2/fr
Publication of WO2005086638A3 publication Critical patent/WO2005086638A3/fr
Priority to IL177444A priority patent/IL177444A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • GPCRs G-protein coupled receptors
  • LPL binds to GPCRs encoded by the Edg gene family, collectively referred to as LPL receptors, to exert diverse biological effects.
  • LPA stimulates phospholipase D activity and PC-3 prostate cell proliferation (Qi et al., "Lysophosphatidic Acid Stimulates Phospholipase 2 D Activity and Cell Proliferation in PC-3 Human Prostate Cancer Cells," J. Cell. Physiol. 174:261-272 (1998)). Further, prior studies have shown that LPA is mitogenic in prostate cancer cells and that PC-3 and DU-145 express LPA1, LPA2, and LPA3 receptors (Daaka, "Mitogenic Action of LPA in Prostate," Biochim. Biophys. Acts 1582:265-269 (2002)).
  • Advanced prostate cancers express LPL receptors and depend on phosphatidylinositol 3- kinase (“PI3K”) signaling for growth and progression to androgen independence (Kue and Daaka, "Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling," J. Ural. 164:2162-2167 (2000)).
  • PI3K phosphatidylinositol 3- kinase
  • a first aspect of the present invention relates to compounds according to formula (I) and formula (II)
  • R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or or-(CH 2 ) m — Y 1 where m is an integer from 0 to 10 and Y 1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R 2 is hydrogen, an aliphatic or non-aliphatic straight- or
  • R3 is hydrogen or an aliphatic or non-aliphatic straight- or branched-chain CI to CIO hydrocarbon
  • R4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl
  • R 5 , R 6 , R 7 , R 8 , R 9 , R ⁇ , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched-
  • a second aspect of the present invention relates to compounds according to formula (V) and formula (VI)
  • X 1 and X 2 are each optional, and each can be oxygen; X 5 is optional, and can be oxygen; R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, R 10 — N(Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated 0-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated
  • R3 is nothing, hydrogen or an aliphatic or non-aliphatic straight- or branched-chain CI to CIO hydrocarbon;
  • R4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched-
  • a third aspect of the present invention relates to compounds according to formula (Nil) wherein X is optional and can be oxygen; X 6 is oxygen or nitrogen; R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, R 10 — (Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated mixed heterocycle;
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, R 10 — (Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbon
  • R is nothing, hydrogen or an aliphatic or non-aliphatic straight- or branched-chain CI to CIO hydrocarbon;
  • R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R u , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched-chain
  • a fourth aspect of the present invention relates to compounds of Formula (VIII)
  • R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated ⁇ -heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or 8 or-(CH 2 ) m — Y 1 where m is an integer from 0 to 10 and Y 1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl
  • a fifth aspect of the present invention relates to compounds having Formula
  • XII wherein X 7 is PO 3 H or O-benzyl; X is O or nothing; R is a CI to C30 aliphatic or non-aliphatic, straight-, cyclic- or branched-chain, substituted or unsubstituted, CI to C30 hydrocarbon; R 17 and R 18 are independently nothing, hydrogen, -SO 2 R 19 , COR 19 , and R 19 ; and R 19 is an aliphatic or non-aliphatic, straight-, cyclic- or branched-chain, substituted or unsubstituted, CI to C30 hydrocarbon or a substituted or unsubstituted aryl.
  • a sixth aspect of the present invention relates to a compound of Formula (XIV) and (XV)
  • a seventh aspect of the present invention relates to a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound according to the first, second, third, fourth, fifth, and sixth aspects of the present invention.
  • a eighth aspect of the present invention relates to a method of destroying a cancer cell that includes the steps of providing a compound according to the first, second, third, fourth, fifth, and sixth aspects of the present invention and contacting a cancer cell with the compound under conditions effective to destroy the contacted cancer cell.
  • a ninth aspect of the present invention relates to a method of treating or preventing a cancerous condition that includes the steps of: providing a compound according to the first, second, third, fourth, fifth, and sixth aspects of the present invention and administering an amount of the compound to a patient in a manner effective to treat or prevent a cancerous condition.
  • a tenth aspect of the present invention relates to a method of making a compound according to formula (I) that includes the steps of: reacting an intermediate according to formula (III),
  • a eleventh aspect of the present invention relates to a method of making a compound according to formula (II) that includes the steps of: reacting an intermediate according to formula (IN),
  • a twelfth aspect of the present invention relates to intermediate compounds according to formula (III) and formula (IV).
  • the present invention affords a significant improvement over previously identified cancer therapeutics that are known to be useful for the inhibition of prostate cancer cell growth.
  • Figure 1 illustrates one approach (scheme 1) for the synthesis of thiazolidine carboxylic acid amides.
  • the thiazolidine carboxylic acid intermediate (2a-v) is formed upon reacting L-cysteine with various aldehydes under reported conditions (Seki et al, "A Novel Synthesis of(+)-Biotin from L-Cysteine,"J. Org. Chem. 67:5527-5536 (2002), which is hereby incorporated by reference in its entirety).
  • FIG. 1 illustrates one approach (scheme 2) for the synthesis of N-30 aryl and - sulfonyl derivatives of the thiazolidine carboxylic acid amides.
  • the N-acyl and N-sulfonyl derivatives (compounds 28 and 29) were synthesized from compound 5 by standard procedures;
  • Figure 3 illustrates one approach (scheme 3) for the synthesis of thiazole carboxylic acid amides.
  • the thiazolidine carboxylic acid methyl ester was converted to the thiazole carboxylic acid methyl ester following a reported procedure (Badr et al friendship "Synthesis of Oxazolidines, Thiazolidines, and 5,6,7,8-Tetrahydro-lH, 3H-pyrrolo[l,2-c] Oxazole (or Thiazole)-!, 3 -diones from ⁇ - ⁇ ydroxy- or j8-Mercapto- ⁇ -amino Acid Esters," Bull. Chem. Soc. Jpn.
  • Figures 4A-B illustrate agarose gel electrophoresis of total DNA extracted from 2 x 10 6 LNCaP cells following treatment with thiazolidine compounds 4 (Figure 4A) and 5 ( Figure 4B) for 24 to 108 hours. The results show the effects of treatment on DNA fragmentation, indicating progression of cell death.
  • the dose and exposure time are indicated for compound 4 as follows: lane 1, 100 bp DNA marker; lane 2, 5 ⁇ M for 36 h; lane 3, 3 ⁇ M for 24 h; lane 4, 3 ⁇ M for 24 h; lane 5, 3 ⁇ M for 48 h; lane 6, 3 ⁇ M for 72 h; lane 7, 3 ⁇ M for 108 h; and lane 8, 50 ⁇ M for 36 h.
  • Figure 4B the dose and exposure time are indicated for compound 5 as follows: lane 1, 100 bp DNA marker; lane 2, 5 ⁇ M for 24 h; lane 3, 5 ⁇ M for 48 h; lane 4, 5 ⁇ M for 72 h; lane 5, 5 ⁇ M for 96 h; lane 6, 3 ⁇ M for 96 h; lane 7, 8 ⁇ M for 48 h; and lane 8, 8 ⁇ M for 72 h;
  • Figures 5A-B demonstrate AKT inhibitory effects of thiazolidine compounds, as measured by inhibition of AKT phosphorylation.
  • Figure 5 A shows the immunoblot results
  • FIG. 12 graphically illustrates the immunological detection of AKT using anti-AKT and anti-phospo- AKT, shown in Figure 5 A;
  • Figure 6 illustrates one approach (scheme 4) for the synthesis of 4-thiazolidinone carboxylic acids, and their conversion to corresponding amides by reaction with primary or secondary amines (HNR2R3).
  • FIG. 7 illustrates a second approach (scheme 5) for the synthesis of 4-thiazolidinone carboxylic acids, and their conversion to corresponding amides by reaction with R 2 -CNO;
  • Figure 8 illustrates three approaches for modifying the core structure of the thiazolidinone compounds of the present invention (scheme 6) to afford ring-bound sulfone or sulfoxide groups (steps a and b, respectively), as well as the complete reduction of carbonyl groups (step c);
  • Figure 9 illustrates a process for the synthesis of polyamine conjugates of thiazolidinone amides;
  • Figure 10 illustrates a scheme for the synthesis of thiazolidinone ethers and esters;
  • Figure 11 illustrates a scheme for the synthesis of oxazoline amides;
  • Figure 12 illustrates a scheme for the synthesis of thiazolidinone dimers;
  • Figure 13 illustrates a scheme for the synthesis of the synthesis of
  • the reagents and conditions can be: (i) CH 3 (CH ) n NH 2 , EDC, HOBt, CH 2 C1 2 , rt, 5 h (ii) TFA, CH 2 C1 2 , rt, 0.5 h (iii) tetrazole, dibenzyl diisopropylphosphoramidite, CH 2 C1 2 , rt, 0.5 h, H 2 O 2 , rt, 0.5 h (iv) H 2 , 10% Pd C, EtOH, rt, 3 h;
  • Figure 14 illustrates a scheme for the synthesis of unsaturated serine amide alcohols and phosphates.
  • the reagents and conditions can be: (i) C 8 H ⁇ (CH: CH)C 8 H ⁇ 6 NH , EDC, HOBt, CH 2 C1 2 , rt, 5 h (ii) 2M HCl/Et 2 O, rt, overnight (iii) tetrazole, di tert butyl diisopropylphosphoramidite, CH C1 , rt, 0.5 h, H O 2 , rt, 0.5 h (iv) TFA, CH 2 C1 2 , rt, 0.5 h;
  • Figure 15 illustrates a scheme for the synthesis of serine diamide phosphates and other amide analogs.
  • Figure 16 illustrates a scheme for the preparation of amino alcohol analogs.
  • the Reagents and conditions (i) TFA, CH 2 C1 2 , rt, 0.5 h (ii) a. LAH, Et 2 O, reflux, 7 h, b. HCI
  • R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, R 10 — N(Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated 0-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated
  • n is an integer from 0 to 10 and Y 2 is a saturated or unsaturated cyclic hydrocarbon, saturated
  • R3 is hydrogen or an aliphatic or non-aliphatic straight- or branched-chain CI to CIO hydrocarbon
  • R4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched-chain CI to CIO hydrocarbon, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalky
  • aliphatic or non-aliphatic straight- or branched-chain hydrocarbon refers to both alkylene groups that contain a single carbon and up to a defined upper limit, as well as alkenyl groups and alkynyl groups that contain two carbons up to the upper limit, whether the carbons are present in a single chain or a branched chain.
  • a hydrocarbon can include up to about 30 carbons, or up to about 20 hydrocarbons, or up to about 10 hydrocarbons.
  • alkyl can be any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified.
  • the alkyl group can be a sole constituent or it can be a component of a larger constituent, such as in an alkoxy, arylalkyl, alkylamino, etc.
  • saturated or unsaturated cyclic hydrocarbons can be any such cyclic hydrocarbon, including but not limited to phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl, 16 cycloalkenyl, cyclodienyl, etc.
  • saturated or unsaturated N-heterocycles can be any such N- containing heterocycle, including but not limited to aza- and diaza-cycloalkyls such as aziridinyl, azetidinyl, diazatidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azocanyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimi
  • heterocycle containing two or more S-, N-, or O-heteroatoms including but not limited to oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, etc.
  • Another aspect of the present invention relates to compounds according to formula (V) and formula (VI)
  • X and X are each optional, and each can be oxygen; X 5 is optional, and can be oxygen; R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or
  • Y 1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, R 10 — N(Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated
  • R 3 is nothing, hydrogen or an aliphatic or non-aliphatic straight- or branched-chain CI to CIO hydrocarbon;
  • R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched
  • Another aspect of the present invention relates to compounds according to formula
  • X 3 is optional and can be oxygen; X is oxygen or nitrogen; / is an integer from 1 to 12; R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated ⁇ -heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, R 10 — ⁇ (Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated 0-heterocycle, a saturated or unsaturated S-heterocycle, a saturated
  • R 3 is nothing, hydrogen or an aliphatic or non-aliphatic straight- or branched-chain CI to CIO hydrocarbon;
  • R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched
  • X 8 is O or S; n is between 1 and 30; R 1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocyeles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non- aliphatic straight- or branched-chain CI to C30 hydrocarbons, or
  • R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched- chain CI to CIO hydrocarbon, aryl, acetyl, or mesyl; and R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight-or branched-chain CI to CIO hydrocarbon, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl
  • R 1 groups include benzyl, furanyl, indolyl, pyridinyl, phenyl, or substituted phenyl (with R 5 -R 9 as defined above).
  • Preferred R 2 groups include aliphatic or non-aliphatic straight- or branched-chain CI to C30 hydrocarbons, phenyl, phenylalkyls, substituted phenyls and substituted phenylalkyls with R ⁇ R 1 groups as defined above.
  • Preferred aliphatic or non-aliphatic straight- or branched-chain hydrocarbons are C8 to C24 hydrocarbons, including CIO to C20 alkyls, more preferably C14 to C18 alkyls.
  • Preferred R 3 groups include hydrogen and CI to CIO alkyls.
  • Preferred R 4 groups include hydrogen, acyl, acetyl, and mesyl.
  • Preferred R 1 groups are polyarnines.
  • the integer / is preferably from 1 to 10, more preferably 1 to 8, 1 to 6, or 1 to 4.
  • the integer In is preferably from 0 to 8, 0 to 6, 0 to 4, or 0 to 2.
  • the integer n is preferably from 0 to 8, 0 to 6, 0 to 4, or 0 to 2.
  • Exemplary compounds according to formula (I) include, without limitation: 2-(4-oxo- 2-phenylthiazolidin-3-yl)acetamide (compound 65), N-decyl-2-(4-oxo-2-phenylthiazolidin-3- yl)acetamide (compound 66), N-tetradecyl-2-(4-oxo-2-phenylthiazolidin-3-yl)acetamide (compound 67), N-octadecyl-2-(4-oxo-2-phenyIthiazolidin-3-yl)acetamide (compound 68), N-octadecyl-2-(4-oxo-2-biphenylthiazolidin-3-yl)acetamide (compound 69), 2-(2-(l-oxo- 2-phenylthiazolidin-3-yl)acetamide (compound 65), N-decyl-2-(4-oxo-2-phenyl
  • Preferred compounds according to formula (I) include compounds 68, 71, 80, and 81.
  • Exemplary compounds according to formula (II) include, without limitation: (4R)-2- (4-methoxyphenyl)-N-octadecylthiazolidine-4-carboxamide (compound 15); (4R)-2-(4- ethoxyphenyl)-N-octadecylthiazolidine-4-carboxamide; N-octadecyl-2-phenyithiazole-4- carboxamide (compound 34); (4R)-2-(3,5-difluorophenyl)-N-octadecylthiazolidine-4- carboxamide (compound 23); (4R)-2-(4-cyanophenyl)-N-octadecylthiazolidine-4- carboxamide (compound 22); (4R)-N-octadecyl-N-mesyl-2-phenylthiazol
  • Compounds of Formula V include, but are not limited to:
  • Compounds of Formula (VII) include, but are not limited to:
  • the intermediate acids can be prepared initially via condensing mercaptoacetic acid, glycine methyl ester, and aromatic aldehydes in a one-pot reaction, followed by basic hydrolysis of the ester (Holmes et al., "Strategies for Combinatorial Organic Synthesis: Solution and Polymer-Supported Synthesis of 4- Thiazolidinones and 4-Metathiazanones Derived from Amino Acids," J Org. Chem. 60:7328-7333 (1995), which is hereby incorporated by reference in its entirety).
  • the thiazolidinone amides of formula (I) can also be prepared by a simple and direct method (Schuemacher et al., "Condensation Between Isocyanates and Carboxylic Acids in the Presence of 4-Dimethylaminopyridine .
  • compound (IN) can be either the R- or S-stereoisomer and R 1 and X 3 are defined as above, with appropriate amines in the presence of EDC/HOBt under standard conditions.
  • the intermediate acids can be prepared via reaction of L-cysteine with desired aldehydes under reported conditions (Seki et al., "A Novel Synthesis of (+)-Biotin from L-Cysteine," J. OGg. Chem. 67:5527-5536 (2002), which is hereby incorporated by reference in its entirety).
  • the compounds of the present invention can also be modified to contain a polymeric conjugate. Suitable polymeric conjugates include, without limitation, poly(alkyl)amines, poly(alkoxy)amine, polyamines, etc.
  • polyamine containing compounds exhibit a number of biological activities and have been utilized as chemotherapeutic agents.
  • exemplary conjugates include those containing the naturally occurring polyamines like putrescine, spermidine, and spermine, as well as synthetic polyamines.
  • a compound of the present invention can be conjugated to a polyamine by reacting the intermediate acid or a nitrophenyl derivative thereof with a polyamine NH 2 -R2 where R 2 is R 10 — N(Z) — hydrocarbon-, or. R 10 -hydrocarbon- , with R 10 and Z being as defined above.
  • An exemplary synthesis scheme is illustrated in Figure 9.
  • compounds of Formulae (V) and (NT) can be formed in accordance with the exemplary synthesis scheme illustrated in Fig. 10.
  • the compound can be made in any other suitable manner.
  • oxazoline analog compounds of Formula (VII) can be formed in accordance with the scheme illustrated in Fig. 11.
  • the compounds of Formula (VII) can be formed using the methods outlined above with respect to the compounds of Formula (II).
  • the compounds may also be made in any other suitable manner.
  • compounds of Fo ⁇ nula (VIII) can be formed in accordance with the scheme illustrated in Fig. 12. Additionally, the compounds can be made in any other suitable manner.
  • compounds of Formulae (IX) and (X) can be made in accordance with the general synthesis of serine amide phosphates (SAPs), serine amide alcohols (SAAs), and serine diamide phosphates (SDAPs) shown in the schemes of Figs. 13-16.
  • SAPs serine amide phosphates
  • SAAs serine amide alcohols
  • SDAPs serine diamide phosphates
  • ⁇ - Boc-serine R or S form
  • the amide is treated with TFA to give an SAA analog.
  • Phosphorylation of the amide and concurrent removal of protecting groups under hydrogenolysis conditions using Pd/C in ethanol gave an SAP.
  • Unsaturated analogues of SAA and SAP can synthesized by similar procedures as shown in the scheme of Fig. 14.
  • Serine diamide phosphates (SDAPs) and other 27 amine derivatives can be synthesized starting from O-benzyl N-Boc-serine as shown in the scheme of Fig. 15.
  • LAH mediated reduction of an amine compound gives long chain N-alkyl amino alcohols as shown in the scheme of Fig. 16.
  • Compounds of Formula (XI) and (XII) which have an ethanolamine amide backbone rather than the serine amide backbone can be synthesized according to the reported procedure Lynch, K. R. H, D. W.Carlisle, S. J.Catalano, J. G.Zhang,
  • the compounds can also be in the form of a salt, preferably a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylie acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylie acid, maleic acid, malonic acid, succinic acid, fumaric acid, tart
  • the compounds of the present invention can be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers.
  • the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stcreoisomer (i.e., substantially pure).
  • substantially pure it is intended that a stereoisomer is at least about 95% pure, more preferably at least about 98% pure, most preferably at least about 99% pure.
  • Another aspect of the present invention relates to pharmaceutical compositions that contain one or more of the above-identified compounds of the present invention.
  • the pharmaceutical composition of the present invention will include a compound of the present invention or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
  • the composition will contain from about 0.01 to about 99 percent or from about 20 to about 75 percent of active compound(s), together with the adjuvants, carriers and/or excipients.
  • application to mucous membranes can be achieved 28 with an aerosol spray containing small particles of a compound of . this invention in a spray or dry powder form.
  • the solid unit dosage forms can be of any suitable type.
  • the solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch.
  • these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.
  • the tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin.
  • a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with
  • a syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor,
  • these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations can contain at least 0.1 % of active compound.
  • the percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 800 mg of active compound.
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable 29 solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient.
  • Such adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components.
  • sterile liquids such as water and oils
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean ail, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • the materials of the present invention also . may be administered in a non- pressurized form such as in a nebulizer or atomizer.
  • the compounds of the present invention are particularly useful in the treatment or prevention of various forms of cancer, particularly prostate cancer, breast cancer, and ovarian cancer. It is believed that other forms of cancer will likewise be treatable or preventable upon administration of the compounds or compositions of the present invention to a patient.
  • a further aspect of the present invention relates to a method of destroying a cancerous cell that includes: providing a compound of the present invention and then contacting a cancerous cell with the compound under conditions effective to destroy the contacted cancerous cell.
  • the cells to be destroyed can be located either in vivo or ex vivo (i.e., in culture).
  • a still further aspect of the present invention relates to a method of treating or preventing a cancerous condition that includes: providing a compound of the present invention and then administering an effective amount of the compound to a patient in a manner effective to treat or prevent a cancerous condition.
  • An effective amoxmt will be understood as referring to an amount of the compound that is effective at reducing, preventing, ameliorating, or improving at least one symptom of the condition for which the compound is administered. It will be further understood that the term "prevent” shall be understood as referring to the prevention of the development of at least one symptom related to the condition for which the compound is administered.
  • the patient to be treated is characterized by the presence of a precancerous condition, and the administering of the compound is effective to prevent development of the precancerous condition into the cancerous condition. This can occur by destroying the precancerous cell prior to or concurrent with its further development into a cancerous state.
  • the patient to be treated is characterized by the presence of a cancerous condition, and the administering of the compound is effective either to cause regression of the cancerous condition or to inhibit growth of the cancerous condition. This preferably occurs by destroying cancer cells, regardless of their location in the patient body. That is, whether the cancer cells are located at a primary tumor site or whether the cancer cells have metastasized and created secondary tumors within the patient body.
  • patient refers to any mammalian patient, including without limitation, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents.
  • administering can be administered systemically or, alternatively, they can be administered directly to a specific site 31 where cancer cells or precancerous cells are present.
  • administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells.
  • Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
  • the pharmaceutical composition can also contain, or can be administered in conjunction with, other therapeutic agents or treatment regimen presently known or hereafter developed for the treatment of various types of cancer.
  • compositions within the scope of this invention include all compositions wherein the compound of the present invention is contained in an amount effective to achieve its intended purpose. While individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.01 to about 100 mg/kg body wt. The most preferred dosages comprise about 0.1 to about 100 mg/kg body wt.
  • Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any side effects.
  • EXAMPLES The Examples set forth below are for illustrative purposes only and are not intended to limit, in any way, the scope of the present invention.
  • Example 1 Synthesis of Thiazolidine Carboxylic Acid Amides All reagents and solvents used were reagent grade or were purified by standard methods before use. Moisture-sensitive reactions were carried under an argon atmosphere. Progress of the reactions was followed by thin-layer chromatography (TLC) analysis. Flash column chromatography was carried out using silica gel (200-425 mesh) supplied by Fisher. Melting points were measured in open capillary tubes on a Thomas-Hoover melting point apparatus and are uncorrected. All compounds were characterized by NMR and MS (ESI). 32 IH NMR spectra were recorded on a Varian 300 instrument. Chemical shifts are reported as S values relative to MeaSi as internal standard.
  • Example 2 Synthesis of N-Acyt and N-sulfonyl Derivatives Thiazolidine Carboxylic Acid Amides
  • N-Acyl and N-sulfonyl derivatives (compounds 28 and 29) were synthesized from compound 5 by standard procedures (scheme 2). Briefly, (2RS, 4R)-2-phenylthiazolidine-4- carboxylic acid octadecylamide (compound 5) was reacted with either acetic anhydride or methyl sulfonyl chloride, in pyridine, to afford the desired derivatives.
  • Example 3 Synthesis of Thiazole Carboxylic Acid Amides
  • the synthesis of thiazole derivative (compound 34) was accomplished starting from cysteine as shown in scheme 3.
  • SOCl 2 (2.76 mL, 37.14 mmol) was slowly added and warmed to room temperature then refluxed for 3 h.
  • the reaction mixture was concentrated in vacuo to yield a residue.
  • Example 4 Analysis of Selected Prostate Cancer Cell Lines by RT-PCR for LPA Receptor Expression DU-145, PC-3, and LNCaP human prostate cancer cells, and RH7777 rat hepatoma cells were obtained from American Type Culture Collection (Manassas, VA). Dr. Mitchell
  • LPAi 0.5 ⁇ g (LPAi) or 1 (LPA 2 and LPA 3 ) of total RNA was used to perform RT-PCR using SuperscriptTM One-Step RT-PCR with Platinum® Tag (Invitrogen Corp., Carlsbad, CA) with 0.2 ⁇ M of primers.
  • LPA reverse 5'-GTGGTCATTGCTGTGAACTCCAGC-3'
  • LPA 2 forward 5'-CTGCTCAGCCGCTCCTATTTG-3'
  • LPA 2 reverse 5'-AGGAGCACCCACAAGTCATCAG-3'
  • LPA 3 forward 5'-CCATAGCAACCTGACCAAAAAGAG-3'
  • LPA 3 reverse 5'-TCCTTGTAGGAGTAGATGATGGGG-3'
  • 3-actin forward 5'-GCTCGTCGTCGACAACGGCTC-3' SEQ ID NO: 7
  • /3-actin reverse 5'-CAAACATGATCTGGGTCATCTTCTC-3' SEQ ID NO: 8).
  • PCR conditions were as follows: After 2 min denaturation step at 94 °C, samples were subjected to 34 to 40 cycles at 94 °C for 30 sec, 60 °C (LPAi) or 58 °C (LPA 2 and LPA 3 ) for 30 sec, and 72 °C for I min, followed by an additional elongation step at 72 °C for 7 min. Primers were selected to span at least one intron of the genomic sequence to detect genomic DNA contamination. The PCR products were separated on 1.5% agarose gels, stained with ethidium bromide, and the band intensity was quantified using Quantity One Software (Bio- Rad Laboratories, Inc., Hercules, CA).
  • LPL receptor expression in these cell lines was determined to validate their use as in vitro models (see Table 2 below). 1 ⁇ g of total RNA was subjected to RT-PCR, the PCR products were separated on agarose gels, and relative expression level of each receptor subtype compared to /3-actin was quantified by Quantity One Software (Bio-Rad). LPAi was the predominant LPL receptor expressed in these cell lines. However, LNCaP cells did not express this receptor subtype. LPA 3 receptor was uniquely expressed in prostate cancer cell lines. RH7777 cells do not express any of the known LPL receptors.
  • Example 5 Cytotoxicity Assay in Prostate Cancer Cells
  • 1000 to 5000 cells were plated into each well of
  • IC 50 concentration that inhibited cell growth by 50% of untreated control
  • IC 50 concentration that inhibited cell growth by 50% of untreated control
  • 5-fluorouracil was used as a positive control to compare potencies of the new compounds.
  • a sandwich ELIS A (Roche, Mannheim, Ge ⁇ nany) utilizing monoclonal antibodies specific for DNA and histones was used to quantify degree of apoptosis induced by the analogs after 72 h exposure. This assay measures DNA-histone complexes (mono- and oligonucleosomes) released into cytoplasm from the nucleus during apoptosis.
  • RH7777 cells were employed because of nonspecific cytotoxicity of compound 4 in receptor-negative cells as well as receptor-positive prostate cancer cells.
  • a control cell line (RH7777) that does not express LPL receptors (Svetlov et al., "EDG Receptors and Hepatic Pathophysiology of LPA and EDG-ology of Liver Injury,” Biochimica et Biophysica ACT 1582:251-256 (2002), which is hereby incorporated by reference in its entirety) was also utilized to understand whether the antiproliferative activity of these derivatives is mediated through inhibition of LPL receptors.
  • the diastereomeric mixtures of the target compounds 3-29 were used as such to evaluate their in vitro inhibitory activity against prostate cancer cell lines, and the results are summarized in Tables 3 and 4 below.
  • IC 0 s should on principle be determined on pure isomers.
  • the IC 5 o values calculated can be used as a screening method to select promising selective cytotoxic agents and to identify the diastereomeric mixture with the best availability to inhibit the growth of prostate cancer cells. Many of these thiazolidine analogs were very effective in killing prostate cancer cell lines with IC50 values in the low/sub micromolar range (Table 3).
  • 43 ring with two chiral centers plays an important role in providing potency and selectivity.
  • Replacements of the phenyl ring with a heterocycle, such as an indole, pyridine or furan ring was investigated by synthesizing analogs (compounds 10-12).
  • the furanyl derivative (compound 12) showed equivalent cytotoxicity as compound 5, but was 3-fold less selective against RH7777 cells.
  • the cytotoxicity data of compounds 13-27 provides a summary of a broad survey of phenyl ring substituted analogs, Examination of the IC 50 values of these analogs demonstrates a greater tolerance for diverse substituents in the phenyl ring.
  • the most potent analogues possessed electron-donating substituents, as exemplified by comparison of compound 13, and compounds 16-18, relative to compound 5.
  • One of the most active compounds (compound 18) with an IC 50 of 0.55 ⁇ M was 38-fold more selective in PPC-1 cells compared to RH7777 cells.
  • thiazolidine analogs (compounds 19-25) with electron-withdrawing substituents demonstrated less cytotoxicity.
  • Comparison of the potencies of compound 26 and compound 27, suggest that substitution of the phenyl ring with a bulky group reduces the activity. From the LPL receptor mRNA expression studies (Table 2), it was evident that these cell lines serve as an excellent model system to explore the effects of LPL receptor.
  • Analog compound 4 induced apoptosis in PC-3 and LNCaP cells, but to a lesser extent in PC-3 cells perhaps due to lower potency in this cell line. This data suggests that thiazolidine analogs may act as potent inducers of apoptosis and selectively kill a variety of prostate cancer cell lines.
  • LNCaP cells were treated with a thiazolidine derivative (compound 4 or 5) for 24 to 108 hours, and then total DNA was extracted from 2 x 10 6 cells by simple centrifugation method, treated with RNase and Proteinase K. After precipication in ethanol, DNA was reconstituted in Tris-EDTA buffer, separated on agarose gels, and visualized by ethidium bromide staining • (Herrmann et al., "A Rapid and Simple Method for the Isolation of Apoptotic DNA Fragments," Nucl. Acids Res.
  • FIG. 5B graphically illustrates the immunological detection of AKT using anti-AKT and anti- phospo-AKT, shown in Figure 5A.
  • Example 6 Synthesis of Thiazolidinone Amides
  • the synthesis of thiazolidinone derivatives utilized straightforward chemistry as shown in scheme 4 ( Figure 6), where is 1.
  • Various 4- thiazolidinones were synthesized following a reported procedure of condensing mercaptoacetic acid, glycine methyl ester, and aromatic aldehydes in a one-pot reaction, followed by basic hydrolysis of the ester (Holmes et al., "Strategies for Combinatorial
  • Example 7 Cytotoxicity Assay The antiproliferative activity of all the synthesized compounds was evaluated against five human prostate cancer cell lines and in RH7777 cells (negative control) using the sulforhodamine B (SRB) assay (see description in Example 5 above). 5-Fluorouracil (5-FU) was used as reference drug. As shown in Table 6, 4-thiazolidinone carboxylic acids
  • Control cell line Prostate cancer cell lines.
  • Example 8 Cytotoxicity Assay in Breast and Ovarian Cancer Cells
  • MCF-7 human breast cancer cell line
  • CHO-I, CaOv-3, SKOv-3, and OVCAR-3 human ovarian cancer cell lines
  • SRB sulforhodamine B
  • Table 8 Antiproliferative effects of compounds on breast and ovarian cancer cell lines Compd ICso ( ⁇ M) MCF-7 a CHO-l CaOv-3 b OVCAR-3 b SKOv-3 b
  • Example 9 Synthesis and Testing of Spermine-coniugated Thiazolidine Amide
  • a mixture of 4-thiazolidinone acid (where R 1 is phenyl and 1 is 1) (1.5 g, 6.32 m mol), 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.51 g, 7.9 m mol) and 1-hydroxybenzotriazole (0.85 g, 6.32 m mol) in CH 2 C1 2 was cooled in an ice bath was sti ⁇ ed for 10 min. To this solution 4-nitrophenol (0.78 g, 5.61 m mot) was added and stirred for 2h.
  • reaction mixture was diluted with CH 2 C1 2 washed sequentially with cold 5% HCt, saturated NaHCO 3 , water, brine, dried (anhydrous Na 2 SO 4 ) and solvent was removed in vacuo.
  • the nitrophenyl ester product (compound 100) was purified by flash chromatography (silica gel) using EtOAc/Hexanes to afford 1.76 g (78%).
  • Compound 101 demonstrated more potent activity against prostate cancer cells compared to ovarian and MCF-7 breast cancer cells, with IC 50 ( ⁇ M) values as follows: 51 RH7777 (>100), DU145 (12.4), PC-3 (11.1), LNCaP (26.2), PPC-1 (11.7), TSU-Prl (5.0), MCF-7 (>100), CaOv-3 (39.3), OVCAR-3 (39.7), and SKOv-3 (>100).
  • Example 10 The antiproliferative effects of 3, 4, 5R, and 5S were compared to that observed with four active serine amide phosphates (SAPs) derivatives and 5-fluorouracil (5-FU, positive control) in human prostate cancer cell lines (PC-3, DU 145, LNCaP, PPC-1, TSU-Prl).
  • a control cell line (RH7777) that does not express LPL receptors 4 and MCF-7 (a human breast cancer cell line) was included to gauge their selectivity.
  • the chosen cell lines represent different basal levels of active AKT and LPL receptor expression (discussed later). Cells were exposed to a wide range of concentrations (0 to 100 ⁇ M) of the indicated compound for 96 h.
  • IC 5 0 i.e., concentration that inhibited cell growth by 50% of untreated control
  • IC 50 values were obtained by nonlinear regression analysis (WinNonlin, Pharsight Corp.).
  • thiazolidine derivatives (3, 4, 5R, and 5S) also potently inhibited prostate and breast cancer cell growth, but were 2- to 12-fold less potent in LPL receptor negative RH7777 cells, suggesting that thiazolidine analogs demonstrate more potent and selective antiproliferative activity.
  • Two important structure-activity relationships were suggested in this small series of compounds. First, analogs containing long alkyl chains (i.e., C ⁇ 8 ; 5R, and 5S) were more potent and selective than derivatives with shorter alkyl chain lengths (i.e., C 7 and C ⁇ ; 3 and 4).
  • the IC 50 for the R-isomer (5R) were less than the IC 5 0 for the S-isomer (5S) in all of the tumor cell lines, except for RH7777. This suggests a stereospecific interaction with a molecular target that is absent or less critical in RH7777 cells.
  • analogs 4, 5R, and 5S were as potent inhibitors of tumor cell proliferation as 5-FU, and were measurably better in many cell lines.
  • Example 11 The cytotoxicity of thiazolidine and SAP derivatives in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, TSU-Prl) and in a negative control cell line (RH7777) that lacks LPL receptor was examined using the sulforhodamine B (SRB) assay.
  • SRB sulforhodamine B
  • Cells were exposed to a wide range of concentrations (0 to 100 ⁇ M) of the particular compound for 96 h in 96 well plates. Cells were fixed with 10% trichloroacetic acid, washed five times with water. The plates were air dried overnight and fixed cells were stained with SRB solution. The cellular protein-bound SRB was measured at 540 nm using a plate reader. Cell numbers at the end of the treatment were measured.
  • IC50 i.e. concentration that inhibited cell growth by 50% of untreated control
  • Example 12 Prostate cell line LNCaP cells were treated with 30 ⁇ M of the compound of Formula:
  • the active form of AKT (Pi- AKT) and the ⁇ -Actin were quantified by Western blot analysis.
  • the compound of Formula VIII had an IC 50 equal to 10.3 ⁇ M. The results of the experiment are given below.
  • Prostate cell line LNCaP cells were treated with 10 ⁇ M of the compound of Formula:
  • Example 14 Prostate cell line LNCaP cells were treated with 10 ⁇ M of the compound of Formula
  • EXAMPLE 15 The cytotoxicity of synthesized compounds in five human prostate cancer cell lines (DU-145,
  • PC-3, LNCaP, PPC-1, and TSU was examined using the sulforhodamine B (SRB) assay (Rubinstein, L. V. S., R. H.Paull, K. D.Simon, R. M.Tosini, S.Skehan, P.Scudiero, D. A.Monks, A.Boyd, M. R. J Natl. Cancer. Inst. 1990, 82, 1113-1118, which is incorporated by reference herein). Cells were exposed to a wide range of concentrations (0 to 100 ⁇ M) of the particular compound for 96 h in 96-well plates.
  • SRB sulforhodamine B
  • IC50 i.e. concentration that inhibited cell growth by 50% of untreated control

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Abstract

La présente invention a trait à des analogues inhibiteurs de la prolifération cellulaire. L'invention a également trait à des procédés de fabrication des analogues. Les analogues peuvent être utilisés pour le traitement de conditions cancéreuses telles que le cancer de la prostate, du sein et de l'ovaire.
PCT/US2005/004759 2004-02-11 2005-02-11 Analogues inhibiteurs de la proliferation cellulaire, leurs procedes de fabrication, et leurs utilisations WO2005086638A2 (fr)

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EA200601471A EA200601471A1 (ru) 2004-02-11 2005-02-11 Ингибиторы клеточной пролиферации клеток (варианты), фармацевтическая композиция на их основе, способ уничтожения раковых клеток (варианты) и способ лечения и профилактики злокачественных состояний (варианты)
AU2005220705A AU2005220705A1 (en) 2004-02-11 2005-02-11 Analogs exhibiting inhibition of cell proliferation, methods of making, and uses thereof
JP2006553347A JP2007522247A (ja) 2004-02-11 2005-02-11 細胞増殖の阻害を示すアナログ、それを作製する方法およびその使用
BRPI0507612-9A BRPI0507612A (pt) 2004-02-11 2005-02-11 análogos exibindo inibição de proliferação de célula e métodos para fabricação e uso destes
EP05749117A EP1723127A4 (fr) 2004-02-11 2005-02-11 Analogues inhibiteurs de la proliferation cellulaire, leurs procedes de fabrication, et leurs utilisations
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KR101395146B1 (ko) * 2011-02-09 2014-05-16 부산대학교 산학협력단 피부미백, 항산화 및 ｐｐａｒ 활성을 갖는 신규 화합물 및 이의 의학적 용도
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EP1723127A4 (fr) 2009-10-28
AU2005220705A1 (en) 2005-09-22
IL177444A0 (en) 2006-12-10
BRPI0507612A (pt) 2007-07-03
EP1723127A2 (fr) 2006-11-22
WO2005086638A3 (fr) 2005-11-24
JP2007522247A (ja) 2007-08-09
EA200601471A1 (ru) 2007-10-26
CA2559333A1 (fr) 2005-09-22

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