MEDICINAL CHEMISTRY
Drugs able to modulate the microtubule assembly either by inhibition of tubulin polymerization or by blocking microtubule disassembly are of great interest in anticancer therapy. Arylthioindoles (ATIs) bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety have proven to be excellent tubulin polymerization inhibitors, with IC50s in the micromolar range. ATIs also inhibit MCF-7 cell growth at nanomolar concentrations, with potencies comparable to the reference compounds colchicine and combretastatin A-4.
PDZ1 targeting NHERF1 inhibitors
Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We reported novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents.
In the search for novel small molecules as alternative modulators of cell death, the recent discovery of a new BAX activation site offered a thrilling opportunity to develop a novel class of alternative apoptosis activators. The identification of the first, and so far still unique, small molecule BAM-7 as BAX direct activator has represented a milestone in the field. Such a compound was used as pharmacological,tool to ascertain, for the first time, the anticancer potential of BAX direct activators; the obtained results would suggest that BAX direct activators are potential future anticancer drugs.
Carbonic anhydrases are metal containing enzymes which catalyze the production of monohydrogen carbonate from carbon dioxide and water. CA XIV isoform is a potential target for the design of agents against epilepsy and some retinopathies. New 1,1′ biphenylsulfonamides were synthesized and evaluated as inhibitors of CA I, II, IX, XII, and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides inhibited all the isoforms, with Ki values in the nanomolar range of concentration, and were superior to AAZ against all of them. X-ray crystallography and molecular modeling studies on the adducts formed by most potent hCA XIV inhibitor of the series (Ki = 0.26 nM) the five hCAs provided insight into the molecular determinants responsible for the high affinity of this molecule toward the target enzymes.
Chronic myelogenous leukemia (CML) is a clonal disease of hemopoietic progenitor cells. CML is characterized by the expression of the BCR-ABL fusion gene, which is derived from the fusion of the cellular breakpoint cluster region (BCR) gene and the Abelson murine leukemia oncogene (ABL). Imatinib is a potent inhibitor in all of the ABL tyrosine kinases, including BCR-ABL. Despite its initial efficacy, IM selects drug resistance due to the emergence of mutation at the kinase domain. PBTDs are a new class of agents with high apoptotic activity in K562 cells and in cells from patients at onset and who were imatinib-resistant. Our results demonstrated that PBTDs induce apoptosis in human BCR-ABL-expressing leukemia cells. The apoptotic activity was observed in primary leukemia blasts, obtained from CML patients at onset or from patients in blast crisis and who were IM-resistant.
The search for anti-AIDS agents led to the development of potent classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs): PBTD, PAS and IAS. The potent activity of IASs against the NNRTI-resistant mutants correlated to the presence of a 3-(3,5-dimethylphenyl)sulfonyl moiety. Potent IAS derivatives were also obtained by adding to the 2-carboxyamide nitrogen natural and unnatural amino acid units to give derivatives with activity against HIV-1 WT and NNRTI-resistant mutants superior to that of the parent indole derivative L-737,126.
Zika virus (ZIKV) infection which initially was endemic only in Africa and Asia, is rapidly spreading throughout Europe, Oceania, and the Americas. Although enormous efforts, there is still no approved drug to treat ZIKV infection. We reported the synthesis and biological evaluation of agents with non-competitive mechanism of the ZIKV NS2B/NS3 protease inhibition through the binding to an allosteric site. Two compounds showed potent activity in both enzymatic and cellular assays. The most active compound efficiently reduced the ZIKV protein synthesis and the RNA replication, and prevented the mice from life-threatening infection and the brain damage caused by ZIKV infection in a ZIKV mouse model.
Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. We identified new compounds with anti-DENV targeting RdRp and NS3 protease, using cell-based reporter assay. These compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication