Synthesis and biological evaluation of imidazoquinoxalinones, imidazole analogues of pyrroloiminoquinone marine natural products.
This report describes the synthesis and biological activity of imidazoquinoxalines, benzimidazole-based analogues of indole-based pyrroloiminoquinone marine natural products. Our analogues consist of series 1, which possesses the ethylene tether and extended amidine feature found in the pyrroloiminoquinone natural products, and series 2, which also has the ethylene tether but with an electrostatically stabilized iminoquinone rather than a resonance stabilized iminoquinone (i.e., extended amidine). The biological properties of series 1 analogues, bearing electron-rich side chain rings (indole and phenol), display cytostatic and cytotoxic properties similar to that of the pyrroloiminoquinone natural products. In contrast, COMPARE analysis suggests that analogues bearing benzyl and phenethyl side chains possess a different cytotoxicity mechanism. Hollow fiber assays of analogs of 1 indicate promising antitumor activity and acceptable levels of toxicity. One analogue of 2 is active only against breast cancer cell lines, but the cellular target is as yet unknown.
Hoang
Hung
H
Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
LaBarbera
Daniel V
DV
Mohammed
Kaleem A
KA
Ireland
Chris M
CM
Skibo
Edward B
EB
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008386:Marine Biology; D051379:Mice; D011758:Pyrroles / Q000737:chemistry*; D015363:Quinolones / Q000737:chemistry*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
D000970:Antineoplastic Agents; D001688:Biological Products; D007093:Imidazoles; D011758:Pyrroles; D015363:Quinolones; D011810:Quinoxalines; C119051:makaluvamine H; D004250:DNA Topoisomerases, Type II