Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of Ludartin.
A convenient and modular synthesis involving diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction was carried out to furnish 1,4-disubstituted-1,2,3-triazoles of Ludartin. This reaction scheme involving Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction leading to the formation of triazolyl analogs is being reported for the first time. All the triazolyl products were characterised using spectral data analysis. Sulphorhodamine B cytotoxicity screening of the resulting products against a panel of five human cancerous cell-lines revealed that few of the analogs display promising broad spectrum cytotoxic effect. Among all the synthesized compounds, only 3q displayed the best cytotoxic effect with IC50 values of 12, 11, 38, 39 and 8.5 μM but less than the standard Ludartin (1) with IC50 values of 6.3, 7.4, 7.5, 6.9 and 0.5 μM against human neuroblastoma (T98G), lung (A-549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines, respectively. The present synthesis was designed based on the previous literature reports of Ludartin as an aromatase inhibitor. Our work provides an initial study on structure-activity relationship of triazolyl analogs of sesquiterpene lactones in general and Ludartin (1) in particular.
Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar 190005, India.
Shabir H
SH
Lone
Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar 190005, India. Electronic address: kabhat@iiim.ac.in.
Khursheed A
KA
Bhat
Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Jammu 180001, India.
Rabiya
R
Majeed
Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Jammu 180001, India.
Abid
A
Hamid
Department of Chemistry, University of Kashmir, Srinagar 190006, India.
Mohd A
MA
Khuroo
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057930:Click Chemistry; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D012717:Sesquiterpenes; D014230:Triazoles; C000592079:ludartin
Cytotoxicity; Huisgen 1,3-dipolar cycloaddition; Ludartin; Michael-addition