Supplementary data for the article: Filipović, N. R.; Bjelogrlić, S.; Portalone, G.; Pelliccia, S.; Silvestri, R.; Klisurić, O.; Senćanski, M.; Stanković, D.; Todorović, T. R.; Muller, C. D. Pro-Apoptotic and pro-Differentiation Induction by 8-Quinolinecarboxaldehyde Selenosemicarbazone and Its Co(III) Complex in Human Cancer Cell Lines. MedChemComm 2016, 7 (8), 1604–1616. https://doi.org/10.1039/c6md00199h

Supplementary material for: [https://doi.org/10.1039/c6md00199h]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2293]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3598

Supplementary data for article: Filipović, N. R.; Bjelogrlić, S. K.; Pelliccia, S.; Jovanović, V. B.; Kojić, M.; Senćanski, M.; La Regina, G.; Silvestri, R.; Muller, C. D.; Todorović, T. R. Selenotriapine - An Isostere of the Most Studied Thiosemicarbazone with Pronounced pro-Apoptotic Activity, Low Toxicity and Ability to Challenge Phenotype Reprogramming of 3-D Mammary Adenocarcinoma Tumors, 2017. https://doi.org/10.1016/j.arabjc.2017.11.017

Supplementary material for: [https://doi.org/10.1016/j.arabjc.2017.11.017]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/320

Supplementary data for the article: Filipović, N. R.; Bjelogrlić, S.; Portalone, G.; Pelliccia, S.; Silvestri, R.; Klisurić, O.; Senćanski, M.; Stanković, D.; Todorović, T. R.; Muller, C. D. Pro-Apoptotic and pro-Differentiation Induction by 8-Quinolinecarboxaldehyde Selenosemicarbazone and Its Co(III) Complex in Human Cancer Cell Lines. MedChemComm 2016, 7 (8), 1604–1616. https://doi.org/10.1039/c6md00199h

Supplementary material for: [https://doi.org/10.1039/c6md00199h]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2293]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3598

Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2–P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2–P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the β-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low μM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics

New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer

Toward highly potent cancer agents by modulating the c-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes

New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway

Drug design, chemical optimization and biological evaluation of pre-existing scaffolds towards selected therapeutic targets.

In this PhD thesis, I have focused my attention on drug design, chemical optimization and biological evaluation of pre-existing scaffolds towards selected therapeutic targets, such as UT-II receptor, tubulin and GSK-3beta. Firstly, I reported the synthesis of potential agonists and antagonists of UT-II receptor. These compounds share a monoketopiperazine scaffold, decorated with appropriate aminoacid residues that are pharmacophoric for UTR-II. Secondly, I presented the results about new 2-heterocyclyl-3-arylthio-1H-indoles as anticancer agents. Some derivatives exhibited potent tubulin assembly and cancer cell growth inhibition in vitro and in vivo assays. Thirdly, I showed the synthesis of new GSK-3beta inhibitors as potential anti-Alzheimer agents. New derivatives were obtained by chemical modification of a recently identified hit compound, leading to a potent GSK-3beta inhibitory activity in the low micromolar range of concentration

On-water pyrrolidine-mediated domino synthesis of 2-iminoisatins

The on-water reaction between 2-(sulfonylamino)-benzaldehydes, isocyanides and pyrrolidine is able to afford a library of poorly synthetically accessible 2-iminoisatins. The pyrrolidine exhibits for the first time the unique role of promoting a triple domino process, i.e.The formation of an N-Alkyl-2,3-diaminoindole, the sulfonamide heterolytic N-S bond cleavage, and the hydrolysis of the resulting iminium ion, with the loss of p-Toluenesulfinic acid. RP HPLC-DAD and UHPLC-HRMS real-Time monitoring of the reaction provided experimental data that support the reaction mechanism. The use of water as a solvent under ultrasound catalysis and the convergent nature of this approach allow, for the first time, a green and sustainable synthesis of 2-iminoisatins