4-aryl/heteroaryl-4H-fused Pyrans as Anti-proliferative Agents: Design, Synthesis and Biological Evaluation

Author(s):

Dinesh Kumar*, Gurpreet Singh, Pooja Sharma, Arem Qayum, Girish Mahajan, M.J. Mintoo, Shashank Kumar Singh, Dilip Manikrao Mondhe, P.M.S. Bedi, Subheet K. Jain and Girish Kumar Gupta   Pages 57 - 73 ( 17 )

Abstract:

Aims: The current study is focused on the design and synthesis of 4-aryl/heteroaryl-4H-fused pyrans as anti-proliferative agents. All the synthesized molecules were screened against a panel of human carcinoma cell lines. </P><P> Description: Significant inhibition was exhibited by the compounds against HCT-116 (Colon) and PC-3 (Prostate) cell lines while A-549 (Lung) cell lines, MiaPaCa-2 (Pancreatic) cell lines and HL-60 (Leukemia Cancer) cell lines were almost resistant to the exposure of the test compounds. Compound FP-(v)n displayed noteworthy cytotoxicity towards HCT-116 malignant cells with the IC50 value of 0.67 &#181;M. It induces apoptosis as revealed by several biological endpoints like apoptotic body formation, through DAPI staining, phase contrast microscopy and mitochondrial membrane potential loss. Moreover FP-(v)n is a potent apoptotic inducer confirmed by cell cycle arrest and ROS generation. The cell phase distribution studies indicate an augment from 4.94 % (control sample) to 39.68 % (sample treated with 1.5 &#181;M compound FP-(v)n) in the apoptotic population. Compound FP-(v)n inhibits the tumor growth in Ehrlich ascites carcinoma (EAC), Ehrlich Tumor (ET, solid) and sarcoma-180 (solid) mice models. Additionally, it was established to be non-toxic at maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. </P><P> Conclusion: The current study provides an insight into anti-cancer potential of FP-(v)n, which might be valuable in the treatment of tumor.

Keywords:

Apoptosis, pyrans, cytotoxicity, cell lines, cell cycle, sarcoma-180, acute toxicity, anti-cancer efficacy.

Affiliation:

Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, Rajendra Institute of Technology and Science, Sirsa, Haryana, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, Indian Institute of Integrative Medicine, Jammu--18001, Indian Institute of Integrative Medicine, Jammu--18001, Indian Institute of Integrative Medicine, Jammu--18001, Indian Institute of Integrative Medicine, Jammu--18001, Indian Institute of Integrative Medicine, Jammu--18001, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, Department of Pharmaceutical Chemistry, M.M.College of Pharmacy, Maharishi Markandeshwar University, Mullana, 133203, Haryana

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