title: A convergent synthesis of alkyne-azide cycloaddition derivatives of 4-α,β-2-propyne podophyllotoxin depicting potent cytotoxic activity.
abstract: A facile synthetic approach to construct the O-propargyl derivatives of 4α and 4β-(1,2,3-triazol-4-yl)-podophyllotoxin (9a-k & 10a-k) and 4'-Demethyl-4'-4β-(1,2,3-triazol-4-yl)-epipodophyllotoxin (12a-d) were synthesized by means of click chemistry. The chemical structures were confirmed by (1)H, (13)C, 2D NMR and HRMS spectral analysis and their cytotoxicities were measured against diverse human cancer cell lines viz. PC-3, PANC-1, COLO-205 and A-549 by MTT assay. Some of the compounds were found more potent than the parent molecule Podophyllotoxin, like; 9a &10a, 9h &10h, 9k &10k, 10d, 8 and 12a. The most potent molecule discovered was compound 9k that exhibited the highest cytotoxicity on all the four cancer cell lines with IC50 values of 3.8-22 nM. The compound further found to induce apoptosis and strongly hindered the motility of aggressive prostate cancer PC-3 cells.
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Zilla
authors.affiliation: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Debasis
authors.initials: D
authors.lastname: Nayak
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Parduman Raj
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Anindya
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: asifali@iiim.ac.in.
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001386:Azides / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: C000593384:4-(O-methyl(orthocyanophenyl-1,2,3-triazol-4yl))podophyllotoxin; D000480:Alkynes; D000970:Antineoplastic Agents; D001386:Azides; D014230:Triazoles; D011034:Podophyllotoxin
keywords: Apoptosis; Migration; Motility; Podophyllotoxin; Triazole