title: Synthesis, spectroscopic, and biological studies of novel estolides derived from anticancer active 4-O-podophyllotoxinyl 12-hydroxyl-octadec-Z-9-enoate.
abstract: Podophyllotoxin is a well-known natural antitumor agent with severe side effects, which led us to synthesize its numerous analogs in search of product(s) of improved therapeutic potential. Here, we report an efficient method for the synthesis of a series of 4-O-podophyllotoxin estolides with spectral characteristics and their biological studies. The OH of a known molecule, 4-O-podophyllotoxinyl 12-hydroxyl-octadec-Z-9-enoate 2, was coupled with the carboxylic groups of different FA with the help of dicyclohexylcarbodiimide and dimethyl aminopyridine (catalyst) to produce high yields of their respective C(4)alpha-estolides 3-11. Spectroscopic techniques, particularly 1H and 13CNMR, proved to be suitable tools to characterize the new compounds. These molecules of greater lipophilic character were tested for their in vitro cytotoxicity against four human solid tumors, one human leukemia cell, and one noncancerobu cell. Compounds 4-6 and 11 showed moderate antileukemic activity; unexpectedly, none were found to be active against solid tumors. Estolides were also investigated for their in vitro activity against tubulin and topoisomerase II proteins. All the compounds showed inhibition of the catalytic activity of topoisomerase II, whereas 6-8 also inhibited tubulin polymerization. These results suggest the need for further screening of these molecules against a larger panel of cancerous cells.
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Jamal
authors.initials: J
authors.lastname: Mustafa
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.forename: Guoyi
authors.initials: G
authors.lastname: Ma
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005227:Fatty Acids; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin