Planta Medica International Open 2016; 3(03): e51-e54
DOI: 10.1055/s-0042-106973
Letter
Georg Thieme Verlag KG Stuttgart · New York

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Shabir H. Lone
1   Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar, India
,
Khursheed A. Bhat
1   Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar, India
,
Fayaz A. Malik
1   Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar, India
,
Mohd A. Khuroo
2   Department of Chemistry, University of Kashmir, Srinagar, India
› Author Affiliations
Further Information

Publication History

received 07 March 2016
revised 25 March 2016

accepted 10 April 2016

Publication Date:
19 August 2016 (online)

Abstract

Diverse 11R,13-dihydroamino and 1,10β-epoxy-11R,13-dihydroamino analogs of ludartin were synthesized using a highly diastereoselective Michael addition and epoxidation reaction. The semisynthetic analogs were characterized using rigorous spectral data analysis. All the compounds were subjected to sulphorhodamine B cytotoxicity screening against a panel of three breast cancer cells, viz., T47D, MCF-7, and MDA-MB 231. Among the synthesized analogs, compounds 11, 19, and 20 proved to be active against the breast cancer cell lines. Compound 11 represents an epoxy analog of arglabin (5), which is a noteworthy and clinically significant antitumor agent and exhibited an IC50s of 0.75 µM and 1.20 µM against MCF-7 and MDA MB-231 cell lines, respectively. Compounds 19 and 20 displayed selectivity among the three breast cancer cell lines and were active against MCF-7 cell lines only displaying IC50s of 1.00 and 1.21 µM, respectively. This study provides initial structure-activity relationship data on ludartin and its analogs against breast cancer cell lines based on the previous literature reports of ludartin as an aromatase inhibitor.

Supporting Information

 
  • References

  • 1 Brueggemeier RW, Hackett JC, Diaz-Cruz ES. Aromatase inhibitors in the treatment of breast cancer. Endocr Rev 2005; 26: 331-345
  • 2 Hong Y, Yu B, Sherman M, Yuan YC, Zhou D, Chen S. Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Mol Endocrinol 2007; 21: 401-414
  • 3 Zhai JD, Li D, Long J, Zhang HL, Lin JP, Qiu CJ, Zhang Q, Chen Y. Biomimetic semisynthesis of arglabin from parthenolide. J Org Chem 2012; 77: 7103-7107
  • 4 Lone SH, Bhat KA, Shakeel-u-Rehman. Majeed R, Hamid A, Khuroo MA. Synthesis and biological evaluation of amino analogs of Ludartin: potent and selective cytotoxic agents. Bioorg Med Chem Lett 2013; 23: 4931-4934
  • 5 Lone SH, Bhat KA, Majeed R, Hamid A, Khuroo MA. Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of Ludartin. Bioorg Med Chem Lett 2014; 24: 1047-1051
  • 6 Lone SH, Bhat KA. Hemisynthesis of a naturally occurring clinically significant antitumor arglabin from ludartin. Tetrahedron Lett 2015; 56: 1908-1910
  • 7 Meunier B, de Visser SP, Shaik S. Mechanism of oxidation reactions catalyzed by cytochrome p 450 enzymes. Chem Rev 2004; 104: 3947
  • 8 Miller WR, Bartlett J, Brodie AM, Brueggemeier RW, di Salle E, Lønning PE, Llombart A, Maass N, Maudelonde T, Sasano H, Goss PE. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter?. Oncologist 2008; 13: 829-837
  • 9 Neves MA, Dinis TC, Colombo G, Sá e Melo ML. Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors. J Med Chem 2009; 52: 143-150
  • 10 Shaikenov TE, Adekenov SM, Belyaev NN, Zakiryanova GK. Mechanism of action of the sesquiterpene from Artemisia glabella “Arglabin” in transformed tumor cells. In: Arglabin. Its structure, properties and usage. Pourtmouth, Virginia: Economy Printing; 1997
  • 11 Muftuoglu Y, Mustata G. Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19). Bioorg Med Chem Lett 2010; 20: 3050-3064
  • 12 Zhangabylov NS, Dederer LY, Gorbacheva LB, Vasilʼeva SV, Terekhov AS, Adekenov SM. Sesquiterpene lactone arglabin influences DNA synthesis in P388 leukaemia cells in vivo . Pharm Chem J 2004; 38: 651-653