WO2013053034A2 - Thiazacridines utilisées dans la thérapie anticancéreuse - Google Patents

Thiazacridines utilisées dans la thérapie anticancéreuse Download PDF

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Publication number
WO2013053034A2
WO2013053034A2 PCT/BR2012/000421 BR2012000421W WO2013053034A2 WO 2013053034 A2 WO2013053034 A2 WO 2013053034A2 BR 2012000421 W BR2012000421 W BR 2012000421W WO 2013053034 A2 WO2013053034 A2 WO 2013053034A2
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WO
WIPO (PCT)
Prior art keywords
acridin
lpsf
thiazolidine
dione
ylmethyl
Prior art date
Application number
PCT/BR2012/000421
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English (en)
Portuguese (pt)
Other versions
WO2013053034A3 (fr
Inventor
GALDINO. Suely LINS
Ivan Da Rocha Pitta
CARMO ALVES DE LIMA. María DO
Marina GALDINO DA ROCHA PITTA
Francisco Washington ARAUJO BARROS
Claudia DO Ó PESSOA
Manoel Odorico DE MORAES FILHO
Maira Galdino DA ROCHA PITTA
Original Assignee
Universidade Federal De Pernambuco - Ufpe
Universidade Federal Do Ceará - Ufc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidade Federal De Pernambuco - Ufpe, Universidade Federal Do Ceará - Ufc filed Critical Universidade Federal De Pernambuco - Ufpe
Publication of WO2013053034A2 publication Critical patent/WO2013053034A2/fr
Publication of WO2013053034A3 publication Critical patent/WO2013053034A3/fr

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Classifications

    • 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
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the synthesis of specific N-acridine thiazolidine derivatives and their respective uses as drugs used in cancer therapy.
  • Acridine derivatives are known to have a broad spectrum of biological activities, such as antimicrobial, antimalarial, antitripanosomal activities (BONSE et al., 1999, J. Med. Chem., V.42, n.26, p.5448-54) , leishmanicide (GIRAULT et al., 2000, J. Med. Chem., v.43, n.14, p.2646-54) and, above all, for their antineoplastic properties.
  • the medicinal interest of acridines dates from 1888, but only in 1913 did these compounds begin to be used in medical practice when Browning discovered the bactericidal action of proflavin c and acriflavin b.
  • Anticancer activity was first considered in 1920. Thereafter, various compounds, natural alkaloids or synthetic molecules, were tested as antitumor agents (DEMEUNYNCK et al., 2001, Curr. Pharm. Des., V.7, p. 1703-24).
  • the cytotoxic properties of acridine compounds depend on their ability to intercalate between DNA base pairs and also to inhibit nucleic acid synthesis by blocking the action of the topoisomerase I and topoisomerase II enzymes (SURDON et al., 2001, Molecules, v.6, p.673-82). Therefore, these compounds exert their primary clinical effects by their ability to interfere with DNA function, either by inhibiting DNA replication or transcription.
  • thiazacridine and imidazacridine derivatives that proved to be very effective in treating cancer.
  • the synthetic route used by the same authors to obtain thiazacridine derivatives began with the oxidation of 9-methyl acridine prepared from diphenylamine to acridine-9-carboxaldehyde followed by a Knoevenagel-type condensation reaction. alkaline with ethyl cyanoacetate to obtain ethyl 2-cyano-acridin-9-yl-acrylate ester.
  • thiazolidine part of the molecule was performed by benzylation of thiazolidine-2,4-dione with benzyl halides in alkaline medium.
  • thiazacridine derivatives were obtained by an addition reaction with ethyl 2-cyano-acridin-9-yl-acrylate ester in the presence of piperidine (PITTA et al, 2002, PI 0203747-5, 2003, PCT / BR03 / 00128; PITTA et al., 2006, PI-0601827-0, PCT / WO 2007/109871 A2.
  • the substances obtained according to this invention comprise a group of N-acridinic thiazolidine derivatives.
  • Ethyl 2-cyano-acridin-9-yl-acrylate derivative (Figure 1) was used in condensation with 3-acridin-9-ylmethyl-thiazolidine-2,4-dione LPSF AA-1A ( Figure 2) to obtain bis-acridinium compound 3-acridin-9-ylmethyl-5-acridin-9-ylmethylene-thiazolidine-2,4-dione LPSF AA-2 ( Figure 3).
  • the ⁇ / s-acridine derivative is obtained by heating 3- (acridin-9-yl-methyl) -thiazolidine-2,4-dione, dissolved in anhydrous ethanol in the presence of piperidine, with 2-cyano-acridin. Ethyl 9-yl-acrylate at a temperature of 80 ° C for 4 hours.
  • HL60 leukemia
  • MDA-MB 435 breast - human
  • HCT-8 human - colon
  • RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% antibiotics, kept in an oven at 37 ° C and an atmosphere containing 5% CO 2 .
  • Cells were plated at a concentration of 0.3 x 10 6 cells / 100 ⁇ L for suspended cells and 0.1 x 10 6 ⁇ 8 / 100 ⁇ for adhered cells.
  • the various compounds were added at different concentrations, ranging from 0.39 - 25ug / mL for pure substances. They were incubated for 72 hours in a 5% CO 2 oven at 37 ° C. At the end of this, the plates were centrifuged and the supernatant removed. Then 200 ⁇ of MTT solution (tetrazolium salt) was added, and the plates were incubated for 3h. The absorbance was read after dissolution of the precipitate with DMSO in a 550nm plate photometer spectrum.
  • MTT solution tetrazolium salt
  • the compounds were diluted to a concentration of 5mg / mL. 100 ⁇ g / mL were tested in single concentration on the following SF295 (CNS) strains; HCT-8 (colon) and MDA-MB-435 (breast). The compounds were selected according to tumor growth inhibition percentage higher than 80% in the cell lines used (GI%> 80%). These compounds were tested for IC50 determination.
  • cytotoxic activity was presented in table 1, which refers to proliferation inhibition (%) performed in duplicate by the MTT method for SF-295 (CNS), HCT-8 (colon carcinoma) and MDA-MB435 (melanoma) cells; doxorubicin was used as a positive control; Table 1 shows that values of 0 - 35% were considered (SA) - No Activity; 36 - 55% (PA) - Little Activity; 56 - 85% (MO) - Moderate Activity; 86 - 100% (MA) - Lots of Activity.
  • the LPSF-AA2 derivative was the most active molecule in this series. All compounds show a selective cytotoxic potential for the HCT-8 cell line, with compound AA6 showing the highest cytotoxic potential for this cell line.
  • the LPSF-AA6 compound with a bromine atom for substituted on the benzylidene ring, was also quite effective. It was the most active for the HCT-8 cell line and the second most active for the SF-295 and MDA-MB435 cell lines.
  • LPSF-AA5 was the least active of all compounds synthesized against cell line HCT-8 and MDA-MB435.
  • LPSF-AA2, LPSF-AA3 and LPSF-AA6 were selected for the determination of IC 5 o (Table 2), since they presented tumor growth inhibition percentage higher than 80% o in the used cell lines.
  • IC50 values (50% inhibitory concentration) and 95% confidence interval (95% CI) performed by the MTT method for cells HL-60 (promyelocytic leukemia), CEM (lymphocytic leukemia), MDA-MB435 (melanoma), HCT-8 (colon carcinoma) and SF-295 (CNS) obtained by nonlinear regression using the GraphPad Prism program
  • LPSF-AA2 had the best IC50 values: 4.4 ⁇ g / mL for MDA-MB435, 4.45 ⁇ g / mL for HCT-8, 7.01 ⁇ g / mL for SF-295 and values greater than 25 ⁇ g / mL for HL-60 and CEM, but still these values are very high when compared to doxorubicone.
  • Figure 1 Representation of ethyl 2-cyano-acridin-9-yl-acrylate ester.
  • Figure 2 Representation of the intermediate acridine molecule: 3-acridin-9-ylmethyl-thiazolidine-2,4-dione - LPSF AA-1 A.
  • Figure 3 Representation of the ⁇ zs-acridine derivative 3-acridm-9-ylmethyl-5-acridin-9-ylmethylene-thiazolidine-2,4-dione - LPSF AA-2.
  • Figure 4 - presents the general structure of seven of the nine synthesized derivatives.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés dérivés de la 3-acrydinylméthyl-thiazolidine-2,4-dione, également appelés thiazacridines, ainsi que leurs procédés respectifs de synthèse chimique et leur utilisation thérapeutique dans le traitement du cancer.
PCT/BR2012/000421 2011-10-10 2012-10-24 Thiazacridines utilisées dans la thérapie anticancéreuse WO2013053034A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI1106333-5 2011-10-10
BRPI1106333 2011-10-10

Publications (2)

Publication Number Publication Date
WO2013053034A2 true WO2013053034A2 (fr) 2013-04-18
WO2013053034A3 WO2013053034A3 (fr) 2013-06-27

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PCT/BR2012/000421 WO2013053034A2 (fr) 2011-10-10 2012-10-24 Thiazacridines utilisées dans la thérapie anticancéreuse

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024058A2 (fr) * 2002-09-10 2004-03-25 Conselho Nacional De Desenvolvimento Científico E Tecnológico - Cnpq Molecules a activite antitumorale, et procede de synthese chimique
WO2007109871A2 (fr) * 2006-03-24 2007-10-04 Universidade Federal De Pernambuco - Ufpe Dérives d'acridine a activite antitumorale

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024058A2 (fr) * 2002-09-10 2004-03-25 Conselho Nacional De Desenvolvimento Científico E Tecnológico - Cnpq Molecules a activite antitumorale, et procede de synthese chimique
WO2007109871A2 (fr) * 2006-03-24 2007-10-04 Universidade Federal De Pernambuco - Ufpe Dérives d'acridine a activite antitumorale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
R.H. MOURAO ET AL.: 'Synthesis and Biological Activity of Novel Acridinylidene and Benzylidene thiazolidinediones' EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol. 40, 2005, pages 1129 - 1133, XP005113105 *
WILLIAM A. DENNY: 'Acridine Derivatives as Chemotherapeutic Agents' CURRENT MEDICINAL CHEMISTRY vol. 9, 2002, pages 1655 - 1665, XP009073854 *

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