title: Synthesis and in vitro cytotoxic activity of N-, F-, and S-ether derivatives of podophyllotoxin fatty acid adducts.
abstract: This paper represents the first synthesis, spectroscopic characterization, and antitumor evaluation of F-, N-, and S-containing C4alpha-FA derivatives of podophyllotoxin. In a synthetic strategy, a FA unit of 4-O-podophyllotoxinyl 12-hydroxyoctadec-Z-9-enoate 2, a derivative of podophyllotoxin, was functionalized at the C-12 position by incorporating the F atom and N-containing moieties. The FA olefin (Z, C-9/C-10) of 2 was hydrogenated to produce a derivative possessing a hydroxy function (C-12) on a saturated C18 FA chain. In another synthetic strategy, two S-ethers of podophyllotoxin (C4alpha) were synthesized from a terminal unsaturated FA analog, 4-O-podophyllotoxinyl undec-10-enoate. Syntheses were achieved through effective synthetic procedures; 1H NMR, 13C NMR, IR, and high-resolution mass data proved excellent tools to characterize these derivatives. In vitro antitumor activity was investigated against a panel of five human neoplastic cell lines, SK-MEL (malignant, melanoma), KB (epidermal carcinoma, oral), BT-549 (ductal carcinoma, breast), SK-OV-3 (ovary carcinoma), and HL-60 (human leukemia). Keeping in view the severe lack of tumor selectivity of podophyllotoxin over normal cells, we assayed new analogs against noncancerous mammalian VERO (African green monkey kidney fibroblast) cell lines to gauge their extent of toxicity. Several of these compounds showed excellent moderation of antitumor activity. In general, we found excellent growth inhibition against the human leukemia cell line (HL-60), particularly for the analogs containing S-ethers and carbamates. None of the compounds were toxic to normal cell lines.
authors: National Center for Natural Product Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors: Jamal
authors: J
authors: Mustafa
authors: Shabana I
authors: SI
authors: Khan
authors: Guoyi
authors: G
authors: Ma
authors: Larry A
authors: LA
authors: Walker
authors: Ikhlas A
authors: IA
authors: Khan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D014709:Vero Cells
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D004987:Ethers; D005227:Fatty Acids; D011034:Podophyllotoxin