Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: Synthesis, cytotoxicity and antitubulin activity

Abstract

A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure-activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC(50) = 2-3 μM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G(2)/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners.

Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors

“…The diverse substituted chalcones E1-E16 were obtained by stirring substituted acetophenones and naphthaldehyde in ethanol at room temperature for 6-8 h. The cyclization different chalcones and methyl 4-hydrazinylbenzoate in refluxing ethanol gives compounds F1-F16. [20][21][22][23][24](ii) EtOH,KOH,room temperature,[6][7][8](iii) EtOH,HAc,80 °C,[20][21][22][23][24](iv) MeOH, N2H4·H2O (80%), DMF,70 °C,[20][21][22][23][24](v) RCHO,EtOH,HOAc,room temperature,[6][7][8] Compounds F1-F16 further reacted with excess hydrazine hydrate (80%) to give the requisite intermediate G1-G16. The desired compounds H1-H32 were generated by the reaction of compounds G1-G16 with substituted benzaldehydes in ethanol for 6-8 h. Purified compounds H1-H32 were finally obtained by chromatography.…”

“…Compound e containing the dihydropyrazole and naphthalene ring showed the highest inhibitory EGFR activity (IC50 = 0.12 μM) [21]. Some naphthalene derivatives have been reported as potent microtubule inhibitors, apoptosis inducers, glutamamide analogues or P-glycoprotein inhibitors [22,23]. On the other hand, the naphthalene ring can be recognized in various biologically active compounds with clinical applications.…”

“…All of these facts encouraged us to integrate these three moieties and screen new benzohydrazide derivatives containing dihydropyrazoles Some naphthalene derivatives have been reported as potent microtubule inhibitors, apoptosis inducers, glutamamide analogues or P-glycoprotein inhibitors [22,23]. On the other hand, the naphthalene ring can be recognized in various biologically active compounds with clinical applications.…”

“…Therefore, preparation and extensive biological evaluations on naphthalene derivatives have continuously attracted our attention [28]. Besides, benzohydrazides are reported to possess a wide variety of biological activities like antiglycation [29], antioxidant [30], antileishmanial [22], antibacterial [31], antifungal [23], antitumor [32] and anticonvulsant [24]. Benzothiazole Schiff bases with diverse biological activities have also been reported [26].…”

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“…Natural (E)-stilbenes, hydroxylated in two to five positions. Stilbenes, such as resveratrol, piceatannol, and pinosylvin, are compounds found in numerous medicinal plants and food products [4][5][6] .…”