Synthesis and biological evaluation of novel hydrazide based cytotoxic agents.
Recently, we designed and synthesized a series of pyrroloquinoxaline compounds with hydrazine moiety linking a nitrogen-containing polycyclic group to a heteroaroyl system. Several derivatives, with attractive drug-like properties, were identified as promising cytotoxic agents, showing excellent potency in a panel of cancer cell lines. In the current study, we synthesized a further 19 new analogues to optimize their physicochemical properties and assess a coherent mechanism of action. Several chemical modifications were made to the reference compounds by varying the fused-ring system and/or the heteroacyl moiety. To evaluate their in vitro activity, we tested these compounds in six human cancer cell lines derived from different origins. Among them, two compounds ( 9 and 12 ) showed similar potency as the reference compounds with IC(50) values in the sub-micromolar range in all cell lines tested. Furthermore, compound 12 showed excellent in vivo efficacy in our preliminary human ovarian cancer mouse xenograft studies. Flow cytometric studies indicated that both derivatives interrupted cell cycle progression in colorectal cancer HCT116 cell lines and ovarian cancer SKOV-3 cells. Further mechanistic studies revealed that 9 and 12 were able to induce reactive oxygen species in SKOV-3 cells with apparently different kinetic patterns. Considering their cytotoxicity profiles in a variety of in vitro and in vivo cancer models, these hydrazide based compounds seem to have considerable potentials as novel chemotherapeutics.
Grande
Fedora
F
University of Southern California, School of Pharmacy, Department of Pharmacology and Pharmaceutical Sciences, Los Angeles, CA 90033, USA.
Yamada
Roppei
R
Cao
Xuefei
X
Aiello
Francesca
F
Garofalo
Antonio
A
Neamati
Nouri
N
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000633:toxicity*; D051379:Mice; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D003603:Cytotoxins; D006834:Hydrazines; D017382:Reactive Oxygen Species