Abstract 1967: Synthesis, in vitro evaluation in ovarian cancer cells and molecular modeling analysis of novel 2-aminothiazole and 2-aminopyridine derivatives
Authors: Naz Shagufta , Nadeem Humaira , sarwar sadia , Paracha Rehan Z. , Yu Jun Q. , Huq Fazlul 
Published: August 2018

Background: Resistance to chemotherapy remains a major hurdle in complete cure against ovarian cancer. Among 75 percent of respondents to chemotherapy, the majority would relapse within two years. Cancer cells can overcome therapy-induced damage by activation of back-up signaling pathways and flexible modulation of affected networks resulting in chemo-resistance. Platinum-based drugs are the most active agents in use against the ovarian cancer. Non platinum-based chemotherapy regimens are usually given in the ‘platinum-resistant' setting.

Methods: A series of N-protected and N-deprotected amino acid derivatives of ethyl-2-aminothiazole-4-carboxylate (4a-d & 6a-d) and 2-aminopyridine (5a-d & 7a-d) have been synthesized and characterized by FT-IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. The compounds were evaluated in silico for selected target inhibition. AutoDockVina virtual screening program was used to target multiple markers in cell signaling pathway (including p110a/PI3K, EGFR, VEGFR, PDGFR, BCR-ABL, RET, c-KIT, c-Raf, ALK, ,B-Raf, , CTLA-4). Anti-tumor activity was determined in parent (A2780) and cisplatin resistant (A2780CISR) ovarian cancer cell lines by MTT reduction assay.Binding affinity data of standard drugs and synthesized compounds 4c, 6b and 7c were compared. Binding mode and 2D interactions of the compounds with p110a isoform of PI3K, EGFR, VEGFR and PDGFR were determined.

Results: Among selected targets, p110a isoform of PI3K is the main target involved in development of ovarian cancer; all three ligands were found to be active against this target. Compound 4c&6b exhibited excellent inhibition of p110a isoform of PI3K with binding energy -8.3 Kcal/mol and -8 Kcal/mol that is comparable to the reference compound i.e. -9.8 Kcal/mol. Overall, compound 4c&6b exhibited greatest inhibition with lowest binding energies against most of the targets.All the tested compounds exhibited dose dependent anti-proliferative effect against both cell lines. IC50 and RF values of cisplatin and tested compounds were determined. Compounds 4c, 6b and 7c showed interesting results as they were more active in cisplatin resistant cell line than in parent cells. The RF values of these compounds were 0.83, 0.46 and 0.53 respectively.

Discussion: RF value of a compound provides an idea if the compound can induce more cell death than corresponding drug in resistant cell lines. RF value less than 1 for a compound/drug is an indication of ability of that compound to bring about more cell death than standard drug in resistant cells. These data warrant further investigations into the mechanism of reversal of resistance induced by potential compounds.

Citation Format: Shagufta Naz, Humaira Nadeem, sadia sarwar, Rehan Z. Paracha, Jun Q. Yu, Fazlul Huq. Synthesis, in vitro evaluation in ovarian cancer cells and molecular modeling analysis of novel 2-aminothiazole and 2-aminopyridine derivatives [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1967.