Design,synthesis, and biological evaluation of 2,3‐diphenyl‐cycloalkyl pyrazole derivatives as potential tubulin polymerization inhibitors

Several novel cycloalkyl‐fused 2,3‐diaryl pyrazole derivatives were designed, synthesized, and evaluated as potential anti‐tubulin agents. Compound A10 exhibited the most potent antiproliferative activity against a panel of cancer lines (IC₅₀ = 0.78–2.42 μM) and low cytotoxicity against 293T & L02 (CC₅₀ values of 131.74 and 174.89 μM, respectively). Moreover, A10 displayed inhibition of tubulin polymerization in vitro, arrested the G2/M phase of the cell cycle, changed morphology of tubulin, increased intracellular reactive oxygen species, and induced apoptosis of HeLa cells. Docking simulation and 3D‐QSAR models were performed to elaborate on the anti‐tubulin mechanism of the derivatives. The inhibition of monoclonal colony formation provided more intuitional data to verify the possibility of A10 as a novel tubulin assembling inhibitor.     

Novel menadione hybrids: Synthesis,anticancer activity,and cell‐based studies

A series of novel menadione‐based triazole hybrids were designed and synthesized by employing copper‐catalyzed azide‐alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data (¹H NMR, ¹³C NMR, IR, and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU‐145), cervical (Hela), breast (MCF‐7), and mouse melanoma (B‐16) using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity. Among the tested compounds, the triazoles 5 and 6 exhibited potent activity against all cell lines. In particular, compound 6 showed higher potency than the standard tamoxifen and parent menadione against MCF‐7 cell line. Flow cytometric analysis revealed that compound 6 arrested cell cycle at G0/G1 phase and induced apoptotic cell death which was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin‐V‐FITC assay. Thus, compound 6 can be considered as lead molecule for further development as potent anticancer therapeutic agent.     

Enhanced anticancer activity of glutamate prodrugs of all‐trans retinoic acid

Objectives All‐trans retinoic acid (ATRA), an active metabolite of vitamin A, is widely used in the treatment of acute promyelocytic leukaemia and myelodysplastic syndrome. However, its high lipophilicity is thought to be responsible for the slow dissolution and low bioavailability following oral administration. In order to obtain compounds with better solubility characteristics to improve the transportation and bioavailability of ATRA, derivatives of ATRA containing glutamic acid or its sodium salt were synthesised. Methods The ATRA derivatives synthesised – all‐trans retinoyl glutamate (RAE) and all‐trans retinoyl sodium glutamate (RAENa₂) – were characterised in terms of melting point, optical rotation, mass spectrometry, NMR and partition coefficient. A liposomal preparation formed from RAE was characterised by particle size and zeta potential. The anti‐tumour activity of RAE and RAENa₂ was compared with that of ATRA in mice bearing S₁₈₀ tumours and their effects on the cell cycle were determined in human pro‐myelocytic leukaemia HL‐60 cells. Key findings RAE and RAENa₂ were more active than ATRA against tumour growth. Flow cytometry indicated that RAE and RAENa₂ induced HL‐60 cell cycle arrest, similar to ATRA. DNA fragmentation studies suggested that apoptosis may be one of the mechanisms responsible for the anti‐tumour activities. Conclusions The two derivatives of ATRA, RAE and RAENa₂, exhibited improved aqueous solubility and were more effective in mice bearing S₁₈₀ tumours.