151409-84-6Relevant articles and documents
Chemoproteomics of an indole-based quinone epoxide identifies druggable vulnerabilities in vancomycin-resistant staphylococcus aureus
Kulkarni, Amogh,Soni, Isha,Kelkar, Dhanashree S.,Dharmaraja, Allimuthu T.,Sankar, Rathinam K.,Beniwal, Gaurav,Rajendran, Abinaya,Tamhankar, Sharvari,Chopra, Sidharth,Kamat, Siddhesh S.,Chakrapani, Harinath
, p. 6785 - 6795 (2019)
The alarming global rise in fatalities from multidrug-resistant Staphylococcus aureus (S. aureus) infections has underscored a need to develop new therapies to address this epidemic. Chemoproteomics is valuable in identifying targets for new drugs in different human diseases including bacterial infections. Targeting functional cysteines is particularly attractive, as they serve critical catalytic functions that enable bacterial survival. Here, we report an indole-based quinone epoxide scaffold with a unique boat-like conformation that allows steric control in modulating thiol reactivity. We extensively characterize a lead compound (4a), which potently inhibits clinically derived vancomycin-resistant S. aureus. Leveraging diverse chemoproteomic platforms, we identify and biochemically validate important transcriptional factors as potent targets of 4a. Interestingly, each identified transcriptional factor has a conserved catalytic cysteine residue that confers antibiotic tolerance to these bacteria. Thus, the chemical tools and biological targets that we describe here prospect new therapeutic paradigms in combatting S. aureus infections.
Novel [(N-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and in silico studies
Abdel-Aziz, Hatem A.,Abo-Ashour, Mahmoud F.,Ahmed, Hanaa Y.,Al-Ansary, Ghada H.,Al-Sanea, Mohammad M.,Al-Warhi, Tarfah,Almahli, Hadia,Alotaibi, Ohoud J.,Elaasser, Mahmoud M.,Eldehna, Wagdy M.
, p. 1300 - 1309 (2020/07/04)
As a continuation for our previous work, a novel set of N-alkylindole-isatin conjugates (7, 8a–c, 9 and 10a–e) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on N-1 of indole motif, with subsequent conjugation with different N-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead VI. The best results were obtained with N-propylindole –5-methylisatin hybrid 8a which displayed broad spectrum anti-proliferative action with efficient sub-panel GI50 (MG-MID) range from 1.33 to 4.23 μM, and promising full-panel GI50 (MG-MID) equals 3.10 μM, at the NCI five-dose assay. Also, hybrid 8a was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid 8a exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC50= 0.85 ± 0.03 and 0.46 ± 0.02 μM, respectively). Interestingly, molecular docking for hybrid 8a in CDK2 and Bcl-2 active sites unveiled that N-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate 8a as a promising lead for further development and optimisation as an efficient antitumor drug.
Design, synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents
Wang, Guangcheng,Li, Chunyan,He, Lin,Lei, Kai,Wang, Fang,Pu, Yuzi,Yang, Zhuang,Cao, Dong,Ma, Liang,Chen, Jinying,Sang, Yun,Liang, Xiaolin,Xiang, Mingli,Peng, Aihua,Wei, Yuquan,Chen, Lijuan
, p. 2060 - 2079 (2014/04/17)
A new series of pyrano chalcone derivatives containing indole moiety (3-42, 49a-49r) were synthesized and evaluated for their antiproliferative activities. Among all the compounds, compound 49b with a propionyloxy group at the 4-position of the left phenyl ring and N-methyl-5-indoly on the right ring displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype, which inhibits cancer cell growth with IC50 values ranging from 0.22 to 1.80 μM. Furthermore, 49b significantly induced cell cycle arrest in G2/M phase and inhibited the polymerization of tubulin. Molecular docking analysis demonstrated the interaction of 49b at the colchicine binding site of tubulin. In experiments in vivo, 49b exerted potent anticancer activity in HepG2 human liver carcinoma in BALB/c nude mice. These results indicated these compounds are promising inhibitors of tubulin polymerization for the potential treatment of cancer.
