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 additional 19 new analogues in order 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 IC50 values in the sub-micromolar range in all cell lines tested. Furthermore, compound 12 exhibited 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 (ROS) in SKOV-3 cells with apparent different kinetic patterns. Considering their cytotoxicity profiles in a variety of in vitro and in vivo cancer models, these hydrazide based compounds appear to have considerable potentials as novel chemotherapeutics.

Synthesis and biological evaluation of novel hydrazide based cytotoxic agents

GRANDE, Fedora;AIELLO, Francesca;GAROFALO, Antonio;
2009

Abstract

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 additional 19 new analogues in order 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 IC50 values in the sub-micromolar range in all cell lines tested. Furthermore, compound 12 exhibited 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 (ROS) in SKOV-3 cells with apparent different kinetic patterns. Considering their cytotoxicity profiles in a variety of in vitro and in vivo cancer models, these hydrazide based compounds appear to have considerable potentials as novel chemotherapeutics.
anticancer drugs; hydrazides; mechanism of activity
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11770/132273
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