- Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues
-
In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel ofin cellulobiological studies, allowing the identification of dual Bcl-xL/Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1versusBcl-xL
- Bignon, Jér?me,Brotin, Emilie,Denoyelle, Christophe,El Dine, Assaad Nasr,Elie, Nicolas,Grée, René,Hachem, Ali,Hedir, Siham,Jouanne, Marie,Justaud, Frédéric,Levoin, Nicolas,Paysant, Hippolyte,Poulain, Laurent,Roisnel, Thierry,Roussi, Fanny,Soulieman, Ali,Tasseau, Olivier,Voisin-Chiret, Anne Sophie,Weiswald, Louis Bastien
-
p. 8968 - 8987
(2021/11/04)
-
- Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition
-
Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV–Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 μM and topoisomerase inhibition results in 10 μM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.
- Ribeiro, Amélia Galdino,Almeida, Sinara M?nica Vitalino de,de Oliveira, Jamerson Ferreira,Souza, Tulio Ricardo Couto de Lima,Santos, Keriolaine Lima dos,Albuquerque, Amanda Pinheiro de Barros,Nogueira, Mariane Cajuba de Britto Lira,Carvalho Junior, Luiz Bezerra de,Moura, Ricardo Olímpio de,da Silva, Aline Caroline,Pereira, Valéria Rêgo Alves,Castro, Maria Carolina Accioly Brelaz de,Lima, Maria do Carmo Alves de
-
-
- Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities
-
A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 μM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 μM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg-1 chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies.
- De Oliveira, Jamerson Ferreira,Da Silva, Anekécia Lauro,Vendramini-Costa, Débora Barbosa,Da Cruz Amorim, Cezar Augusto,Campos, Júlia Furtado,Ribeiro, Amélia Galdino,De Moura, Ricardo Olímpio,Neves, Jorge Luiz,Ruiz, Ana Lúcia Tasca Gois,De Carvalho, Jo?o Ernesto,Alves De Lima, Maria Do Carmo
-
p. 148 - 156
(2015/10/29)
-
- Synthesis and structure-activity evaluation of isatin-β- thiosemicarbazones with improved selective activity toward multidrug-resistant cells expressing P-glycoprotein
-
Cancer multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters presents a significant unresolved clinical challenge. One strategy to resolve MDR is to develop compounds that selectively kill cells overexpressing the efflux transport
- Hall, Matthew D.,Brimacombe, Kyle R.,Varonka, Matthew S.,Pluchino, Kristen M.,Monda, Julie K.,Li, Jiayang,Walsh, Martin J.,Boxer, Matthew B.,Warren, Timothy H.,Fales, Henry M.,Gottesman, Michael M.
-
experimental part
p. 5878 - 5889
(2011/10/08)
-
- 2-Acetylpyridine thiosemicarbazones. 1. A new class of potential antimalarial agents
-
Based on the antimalarial properties observed for 2-acetylpyridine 4-phenyl-3-thiosemicarbazone (1), an extensive series of related thiosemicarbazones was prepared and tested against Plasmodium berghei in mice. Screening results indicated that the presence of the 2-pyridylethylidene group was critical and that certain phenyl, benzyl, phenethyl, or cycloalkyl groups at N4 of the thiosemicarbazone moiety also contribute to antimalarial activity.
- Klayman,Bartosevich,Griffin,Mason,Scovill
-
p. 855 - 862
(2007/10/04)
-