- Design, synthesis and biological evaluation of new β-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors
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A series of new β-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 μM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV–Visible, fluorescence, circular dichroism and molecular docking studies revealed that the β-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.
- Kovvuri, Jeshma,Nagaraju, Burri,Nayak, V. Lakshma,Akunuri, Ravikumar,Rao, M.P. Narasimha,Ajitha, Ayyappan,Nagesh, Narayan,Kamal, Ahmed
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- Development of β-carboline-benzothiazole hybrids via carboxamide formation as cytotoxic agents: DNA intercalative topoisomerase IIα inhibition and apoptosis induction
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In quest of promising anticancer agents, the pharmacophores of natural (β-carboline) and synthetic origin (benzothiazole) were adjoined by a carboxamide bridge and three-point diversification was accomplished. The in vitro cytotoxic ability of the compounds was established on adherent and suspension human cancer cell lines and compounds 8u and 8f advanced as pre-eminent molecules with IC50 values of 1.46 and 1.81 μM respectively in A549 cell line. The cytospecificity was entrenched for potent compounds 8u and 8f by evaluating against normal human lung epithelial cells and selectivity index was calculated. Furthermore, EtBr displacement, relative viscosity and gel-based topoisomerase II target assays unveiled the intercalative topo-II inhibitory capability and DNA binding studies (absorbance) revealed the dissociation constant (Kd) for compounds 8u and 8f as 98 and 103 μM respectively. Additionally, cell-based flow cytometric assays like Annexin-V/PI dual staining aids in the quantification of apoptosis induced and JC-1 staining disclosed the depolarization of mitochondrial membrane potential by compound 8u in A549 cells in a dose-dependent manner. Moreover, wound healing assay established the inhibition of in vitro cell migration by compound 8u on A549 cells. In addition, molecular docking studies proved the binding of compounds 8u and 8f in the active site of DNA complexed with topo IIα and stabilized by interactions with DNA base pairs and amino acid residues. Remarkably, the compounds 8u and 8f follow Lipinski's rule of five and are in the recommended range for Jorgensen's rule of three with a minimal violation and other pharmacokinetic parameters revealing druggability of the synthesized hybrids.
- Tokala, Ramya,Mahajan, Surbhi,Kiranmai, Gaddam,Sigalapalli, Dilep Kumar,Sana, Sravani,John, Stephy Elza,Nagesh, Narayana,Shankaraiah, Nagula
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- Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity
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The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged β-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a–k, with an IC50 50 value of 2.82 ± 0.10 μM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 μM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 μM) with a selectivity index range of 14.9–25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
- Tokala, Ramya,Sana, Sravani,Lakshmi, Uppu Jaya,Sankarana, Prasanthi,Sigalapalli, Dilep Kumar,Gadewal, Nikhil,Kode, Jyoti,Shankaraiah, Nagula
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- Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors
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A series of new podophyllotoxin linked β-carboline congeners have been synthesized by coupling various substituted β-carboline acids with 4β-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC50 values of 1.07 ± 0.07 μM and 1.14 ± 0.16 respectively against DU-145 cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.
- Sathish, Manda,Kavitha, Botla,Nayak, V. Lakshma,Tangella, Yellaiah,Ajitha, Ayyappan,Nekkanti, Shalini,Alarifi, Abdullah,Shankaraiah, Nagula,Nagesh, Narayana,Kamal, Ahmed
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p. 557 - 571
(2018/01/01)
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- Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells
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A series of novel β-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these β-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC50 values of 0.53–1.56 μM, which was considerably more potent than harmine (IC50 = 46.7–55.3 μM) and also three-to ten-fold lower than that of SAHA (IC50 = 4.48–6.26 μM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and α-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway.
- Ling, Yong,Guo, Jing,Yang, Qiuxing,Zhu, Peng,Miao, Jiefei,Gao, Weijie,Peng, Yanfu,Yang, Jiaying,Xu, Kun,Xiong, Biao,Liu, Gongqing,Tao, Jinhua,Luo, Lin,Zhu, Qing,Zhang, Yanan
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p. 398 - 409
(2018/01/01)
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- Synthesis of fused tetrahydro-β-carbolinequinoxalinones in 1-n-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide ([bdmim][Tf2N]) and 1-n-butyl-2,3-dimethylimidazolium perfluorobutylsulfonate ([bdmim][PFBuSO3]) ionic liquids
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Starting from tryptophan methyl ester, a three-step synthesis of fused tetrahydro-β-carbolinequinoxalinones in two new ionic liquids, [bdmim][Tf2N] and [bdmim][PFBuSO3], was described. Both ionic liquids can be readily prepared from commercially available starting materials in high yields. Unlike the commonly used [PF6]-based ionic liquids that evidently undergo slow hydrolysis of the PF6 anion with the concomitant release of HF, ionic liquids of [bdmim][Tf2N] and [bdmim][PFBuSO3] are not only chemically stable but also apparently inert to hydrolysis and therefore organic reactions carried out in both ionic liquids proceed smoothly with good yields. The overall isolated yields for this three-step synthesis of tetrahydro-β-carbolinequinoxalinones were 34-55%. To the best of our knowledge, the preparation of fused tetrahydro-β- carbolinequinoxalinones was unprecedented.
- Tseng, Ming-Chung,Liang, Yang-Min,Chu, Yen-Ho
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p. 6131 - 6136
(2007/10/03)
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