WO2002085848A2 - Synthesis of pancratistatin prodrugs - Google Patents
Synthesis of pancratistatin prodrugs Download PDFInfo
- Publication number
- WO2002085848A2 WO2002085848A2 PCT/US2002/011964 US0211964W WO02085848A2 WO 2002085848 A2 WO2002085848 A2 WO 2002085848A2 US 0211964 W US0211964 W US 0211964W WO 02085848 A2 WO02085848 A2 WO 02085848A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pancratistatin
- phosphate
- sodium methoxide
- dibenzyl
- prodrug
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates generally to the discovery of a new and efficient synthesis of the (+)- ⁇ ancratistatin phosphate prodrug and fourteen (14) metal and ammonium cation derivatives thereof.
- the pancratistatin phosphate prodrug denominated 2a in the enclosed Scheme was found to have exceptional solubility in water and therefore readily administerable in the treatment of human cancer.
- the anti cancer phenanthridone (+)-pancratistatin (la) was isolated from the bulbs of the Hawaiian Hymenocallis (formally Pancratium) littoralis (Pettit et al., 1984a, Journal of the Chemical Society, Chemical Communications, 1693; Pettit et al, 1984b, Journal oj Natural Products, 41, 1018). The structure was determined by NMR spectroscopy and confirmed by x-ray crystallographic analysis of its 7-methoxy derivative (lb).
- pancratistatin (la) was found to exhibit strong in vitro cancer cell growth inhibitory activities including against the U.S. National Cancer Institute (NCI) panel of cancer cell lines (Pettit et al, 1986, Journal of Natural Products, 49, 995; 1993 Journal of Natural Products, 56, 1682) and a series of in vivo experimental cancer systems.
- NCI National Cancer Institute
- a related area of promise involves its activity against a range of RNA viruses (Gabrielsen et al, 1992, Journal of Natural Products, 55, 1569). Due to the relatively low natural abundance ( ⁇ 0.039% of dry bulb) and its increasing potential as a clinically useful antitumor agent, pancratistatin has become an important target for total synthesis.
- pancratistatin (la) pancratistatin (la) was earlier hampered due to its poor solubility in water ( ⁇ 53 ⁇ g/ml). This problem was addressed (Pettit et al, 1995a, Anti-Cancer Drug Design, 10, 243) by developing a synthesis of the phosphate prodrug (2a) which displayed greatly improved solubility characteristics in water and was found to exhibit equal activity against the murine P388 lymphocytic leukemia cell. Presumably, attachment of a phosphate is also beneficial for in vivo systems since human non-specific phosphatases will hydrolyze the phosphate prodrug following administration to release (+) -pancratistatin (l ).
- Fig. 1 is a schematic showing of the step-by-step synthesis of the present invention. Detailed Description Of Preferred Embodiment
- (+)-Pancratistatin (la) was isolated from Hymenocallis littoralis as previously described (Pettit et al, 1995b, Journal of Natural Products, 58, 37).
- Acetic anhydride, pyridine, dibenzyl phosphite, N-ethyldiisopropylamine and 10% palladium over carbon catalyst were purchased from Lancaster Synthesis, Inc.
- Carbon tetrachloride, 4-dimethylaminopyridine, anhydrous magnesium sulfate (MgSO 4 ), potassium dihydrogenphosphate, phosphomolybdic acid, and zinc acetate dihydrate were from Sigma- Aldrich Chemical Co.
- Sodium methoxide, lithium hydroxide monohydrate, piperazine (anhydrous) and morpholine were from Acros Organics.
- Calcium acetate and manganese acetate were purchased from Fisher Scientific Co. and magnesium acetate quinine, quinidine and imidazole from J. T. Baker Chem. Rubidium carbonate and cesium carbonate were supplied by Alfa Products, Inc. and potassium acetate from Mallinckrodt. All solvents were redistilled prior to use and dried when necessary. Solvent extracts of aqueous solutions were dried over magnesium sulfate.
- the 1 ,0 M solutions of the metal bases were prepared in distilled water and the 1.0 M solutions of the amines in dry methanol.
- sodium methoxide 87 mg, 1.61 mol
- the mixture was stirred at room ' temperature for 2 hours and then water (50 ml) was added.
- the aqueous mixture was extracted with dichloromethane (5 x 50 ml) and the combined organic extract was dried, filtered and evaporated in vacuo (NO HEAT) to give the crude deacetylated derivative as a white powder (1.8 g).
- pancratistatin prodrugs (2b-o) Following General procedure for synthesis of the pancratistatin prodrugs (2b-o): To an aqueous methanol solution of the phosphoric acid derivative of pancratistatin (6, 50 mg in 1 ml water or methanol) was added a 1.0 M solution (250 ⁇ l) of the appropriate metal (carbonate or acetate) salt or amine free base. The solution became cloudy and the mixture was stirred for 6 hours. The mixture was freeze dried (or evaporated) to afford the desired prodrug salt (2b-o). The salts were further purified by trituration with wet methanol and/or diethyl- ether to remove un-reacted starting materials.
- pancratistatin 7-O-phosphate (2e) Yellow oil (0.22 g); ⁇ /ppm (300 MHz, D 2 O) 6.63 (IH, bs, H-10), 6.01 (IH, s, OCH ⁇ H B O), 5.90 (IH, s, OCH A H 5 ⁇ ), 4.46 (1 ⁇ , bs, ⁇ -l), 4.17 (1 ⁇ , bs, ⁇ -2), 3.98 (1 ⁇ , bs, ⁇ -3), 3.85 (IH, m, H-4), 3.79 (IH, m, H-4a), 3.08 (IH, d, J 12 Hz, H-lOb); m/z (FAB) 669.9 [(M + H) + , 50%], 225.0 (100); HRFAB 669.8468 calculated for
- OCH_H B O 5.96 (IH, s, OCH A H 5 O), 4.41 (1 ⁇ , bs, ⁇ -l), 4.14 (1 ⁇ , bs, ⁇ -2), 3.97 (l ⁇ , bs, H-3), 3.76 (2H, m, H-4, H-4a), 3.41 (IH, d, J l l Hz, H-lOb).
- pancratistatin (la) was simply allowed to react with acetic anhydride and 4-dimethylaminopyridine in pyridine to give the 1,2,3,4,7-O-pentaacetoxy derivative (3) and then immediately converted to the desired 1,2,3,4-O-tetraacetate (4) by heating in refluxing water-pyridine (66% yield).
- Reaction of the latter with dibenzyl phosphite in the presence of carbon tetrachloride, N-ethyldiisopropylamine and 4-dimethylaminopyridine afforded the heat sensitive pancratistatin 7-0- dibenzylphosphate (5) in 87%) yield.
- prodrug derivatives exhibited activities analogous to that of (+)-pancratistatin (la) and the sodium prodrug (2a).
- manganese (2i) and morpholine (2k) derivatives showed a 10- to 20-fold increase in activity, their poor water solubility made questionable their use for further preclinical development as potential prodrugs.
- the sodium derivative (2a) continues to be the preferred choice owing to its high activity, adequate water solubility, and the efficient synthesis described herein.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002583375A JP2005515958A (en) | 2002-04-17 | 2002-04-17 | Synthesis of panclastatin prodrug |
CA002444471A CA2444471A1 (en) | 2001-04-18 | 2002-04-17 | Synthesis of pancratistatin prodrugs |
US10/475,061 US20040127467A1 (en) | 2002-04-17 | 2002-04-17 | Synthesis of pancratistatin prodrugs |
EP02733993A EP1385846A4 (en) | 2001-04-18 | 2002-04-17 | Synthesis of pancratistatin prodrugs |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28471701P | 2001-04-18 | 2001-04-18 | |
US60/284,717 | 2001-04-18 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2002085848A2 true WO2002085848A2 (en) | 2002-10-31 |
WO2002085848A3 WO2002085848A3 (en) | 2003-04-24 |
WO2002085848A8 WO2002085848A8 (en) | 2003-05-30 |
Family
ID=23091255
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/011964 WO2002085848A2 (en) | 2001-04-18 | 2002-04-17 | Synthesis of pancratistatin prodrugs |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1385846A4 (en) |
CA (1) | CA2444471A1 (en) |
WO (1) | WO2002085848A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5529989A (en) * | 1995-01-09 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Pancratistatin prodrug |
-
2002
- 2002-04-17 WO PCT/US2002/011964 patent/WO2002085848A2/en active Application Filing
- 2002-04-17 CA CA002444471A patent/CA2444471A1/en not_active Abandoned
- 2002-04-17 EP EP02733993A patent/EP1385846A4/en not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
PETTIT G.R.: 'Antineoplastic agents 320: synthesis of a practical pancratistatin prodrug' ANTI-CANCER DRUG RES. vol. 10, no. 3, 1995, pages 243 - 250, XP002958298 * |
See also references of EP1385846A2 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
Also Published As
Publication number | Publication date |
---|---|
EP1385846A2 (en) | 2004-02-04 |
WO2002085848A3 (en) | 2003-04-24 |
EP1385846A4 (en) | 2005-11-30 |
WO2002085848A8 (en) | 2003-05-30 |
CA2444471A1 (en) | 2002-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4904768A (en) | Epipodophyllotoxin glucoside 4'-phosphate derivatives | |
Stawinski et al. | Nucleoside H-phosphonates. 12. Synthesis of nucleoside 3'-(hydrogen phosphonothioate) monoesters via phosphinate intermediates | |
EP1504014B1 (en) | Process for preparation of cyclic prodrugs of pmea and pmpa | |
US20020119951A1 (en) | Efficient method of synthesizing combretastatin A-4 prodrugs | |
Stawinski et al. | Nucleoside H-phosphonates. 14. Synthesis of nucleoside phosphoroselenoates and phosphorothioselenoates via stereospecific selenization of the corresponding H-phosphonate and H-phosphonothioate diesters with the aid of new selenium-transfer reagent, 3H-1, 2-benzothiaselenol-3-one | |
US4873355A (en) | Process for regioselectively preparing phosphorylated inositols and other cyclitols | |
PT98590B (en) | (2R) -2- [2- (2-PROPYL) PHOSPHONYMETHOXY] -3-P-TOLUENE-SULFONYLOXY-1-TRIMETHYLCETETOXYPROPANE AND OF BASES (S) -N- (3-HYDROXY-2-PHOSPHONYL METHOXYPROPYL) BASES PURE AND PYRIMIDIC HETEROCYCLICS | |
US20040127467A1 (en) | Synthesis of pancratistatin prodrugs | |
WO2002085848A2 (en) | Synthesis of pancratistatin prodrugs | |
US4924023A (en) | Phosphorylated inositols | |
Lee et al. | Synthesis of nucleoside 3'-alkylphosphonates: intermediates for assembly of carbon-bridge dinucleotide analogs | |
KR900002709B1 (en) | Synthesis of purin-9-ylalkyle-neoxymethyl phosphonic acids | |
Endová et al. | 2′, 3′-O-Phosphonoalkylidene derivatives of ribonucleosides: Synthesis and reactivity | |
Rakhit et al. | Phospholipids. Part I. Synthesis of phosphatidyl ethanolamines | |
Holý | Synthesis of 3-amino-and 3-azidoanalogs of 9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine (HPMPA) | |
Pettit et al. | Anticancer, pancratistatin, phosphate prodrugs, phosphorylation | |
EP1585750A2 (en) | Narcistatin prodrugs | |
JP2005515958A (en) | Synthesis of panclastatin prodrug | |
Scheigetz et al. | Synthesis of fluorescein phosphates and sulfates | |
Legrand et al. | Totally Regio‐and Stereoselective P–O‐to‐P–C Rearrangement in the Synthesis of Chiral P‐(o‐Hydroxyaryl) diazaphospholidine P‐Oxides | |
Chapman et al. | Activated phosphate triesters. Synthesis and reactivity of N-hydroxysuccinimide and N-mercaptosuccinimide esters | |
EP0367189A2 (en) | Sugar phosphates and sulfonates of epipodophyllotoxin glucosides | |
EP0433678A1 (en) | Alkoxymethylidene epipodophyllotoxin glucosides | |
Krečmerová et al. | Preparation of Purine 2'-Deoxy-5'-O-phosphonomethylnucleosides and 2'-Deoxy-3'-O-phosphonomethylnucleosides | |
EP0511563A1 (en) | Process for the preparation of 4'-demethylepipodophyllotoxin glucoside 4'-phosphates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
CFP | Corrected version of a pamphlet front page | ||
CR1 | Correction of entry in section i |
Free format text: IN PCT GAZETTE 44/2002 UNDER (30) REPLACE "**" BY "US" |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002583375 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2444471 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10475061 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002733993 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002733993 Country of ref document: EP |