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We designed new 3-arylthio- and 3-aroyl-1 H -indole derivatives 3–22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1 H -indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13  at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC 50  = 20 nM), 13 was 4-fold superior to 19 . Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents. [ABSTRACT FROM AUTHOR]

Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 μM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 μM), capable of inhibiting the target in cells. [ABSTRACT FROM AUTHOR]

We synthesized 3-aroyl-1-arylpyrrole(ARAP) derivatives as potential anticancer agents having differentsubstituents at the pendant 1-phenyl ring. Both the 1-phenyl ringand 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory toachieve potent inhibition of tubulin polymerization, binding of colchicineto tubulin, and cancer cell growth. ARAP 22showed stronginhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDRcell lines. Compounds 22and 27suppressedin vitro the Hedgehog signaling pathway, strongly reducing luciferaseactivity in SAG treated NIH3T3 Shh-Light II cells, and inhibited thegrowth of medulloblastoma D283 cells at nanomolar concentrations.ARAPs 22and 27represent a new potent classof tubulin polymerization and cancer cell growth inhibitors with thepotential to inhibit the Hedgehog signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. [Copyright &y& Elsevier]