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Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

ABSTRACT: In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC(50) 0.08-1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH(3) in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.

SUBMITTER: Lee CL

PROVIDER: S-EPMC3362575 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

Lee Chia-Lin CL Lin Ying-Ting YT Chang Fang-Rong FR Chen Guan-Yu GY Backlund Anders A Yang Juan-Chang JC Chen Shu-Li SL Wu Yang-Chang YC

PloS one 20120529 5

In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC(50) 0.08-1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer ...[more]

PMID: 22666407

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Project description:A receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew's correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis.

Dataset Information

Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

Publications

Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

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