title: Synthetic modification of hydroxychavicol by Mannich reaction and alkyne-azide cycloaddition derivatives depicting cytotoxic potential.
abstract: Here we report the design, synthesis and lead optimization of hydroxychavicol (1) a high yielding metabolite ubiquitously present in the Piper betel leaves with the significant cytotoxic activity. This is the first report to describe the synthetic strategies of two distinct series of hydroxychavicol by Mannich reaction (2-10) and alkyne-azide cycloaddition (11-20). Furthermore, all the synthesized derivatives along with parent compound were evaluated for their in-vitro cytotoxic and antiproliferative potential in several distinct cancers cell lines. Among all, the Mannich reaction derived molecules 6, 8 and 10 displayed more potent cytotoxic activities with IC50 value in a range from 3 to 9 μM, which were 7-10 fold more potent than 1 against five human cancer cell lines viz. HL-60, Mia PaCa-2, MCF-7, HEP G2 and SK-N-SH. Our results describe an efficient synthetic approach used to evaluate the structure activity relationship of 1 and its derivative in search of potential new anticancer agents.
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Anoop S
authors.initials: AS
authors.lastname: Pathania
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Satti
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Parbhu
authors.initials: P
authors.lastname: Dutt
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Fayaz A
authors.initials: FA
authors.lastname: Mallik
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*; D001386:Azides / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D005054:Eugenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D001386:Azides; C051268:2-hydroxychavicol; D005054:Eugenol
keywords: Click chemistry; Cytotoxicity; Hydroxychavicol; Mannich reaction; Piper betel