Ovarian cancer (OC) is worldwide the deadliest gynaecological cancer. Despite advances in technology and chemotherapy, there has been no significant decrease in the mortality rate from this disease, which frequently presents at an advanced stage. Consequently there has been considerable interest in the development of screening methods to detect such a disease at an earlier stage when treatment is more effective and the mortality rate may be reduced. Currently, advanced epithelial OC is diagnosed following measurements of serum cancer antigen 125 (CA-125), which is over expressed in 85% of epithelial OC and it is routinely used to follow response to treatment.1 Complementary to genomics field, new proteomics technologies are under development to identify protein expression, under different physiological conditions: the diagnostic endpoint for OC is not a single biomarker but rather a proteomic pattern, comprising low molecular weight peptides and cleaved proteins.2 Proteomics analysis allows the identification of proteins in response to the treatment. Recently, a new class of pyrroloquinoxaline based compounds with anticancer activity has been identified. The representative example of this series is SN144, a compound selected as a lead, which offers promising pharmacological and pharmacokinetic properties in terms of activity and oral bioavailability. Flow cytometric analysis of DNA profiles shows that SN144 causes cell cycle arrest in the S-phase, this property makes it a potentially ideal agent for combination chemotherapy with agents acting at different stages of cell cycle. Moreover, SN144 induced a clear up-regulation of some proteins implicated in cellular death by apoptosis in treated OC cells. A series of structurally related compounds has been prepared, in order to establish a coherent mode of action and structure-activity relationship. Their peculiar structural feature is the presence of a hydrazine group linking the pyrroloquinoxaline system to an heteroacyl or aminoacyl moiety. The effect of chemical alterations on these analogs are currently under investigation. References 1 J. L. Wilder, E. Pavlik, et al., Gynecol Oncol, 89, 233 (2003). 2 E. F. Petircoin, L. A. Liotta, Molecular Medicine, 10, 2, 59 (2004).
Design of novel drugs against ovarian cancer: synthesis of Pyrroloquinoxalinylacylhydrazines
GRANDE, Fedora;AIELLO, Francesca;A. GAROFALO
2004-01-01
Abstract
Ovarian cancer (OC) is worldwide the deadliest gynaecological cancer. Despite advances in technology and chemotherapy, there has been no significant decrease in the mortality rate from this disease, which frequently presents at an advanced stage. Consequently there has been considerable interest in the development of screening methods to detect such a disease at an earlier stage when treatment is more effective and the mortality rate may be reduced. Currently, advanced epithelial OC is diagnosed following measurements of serum cancer antigen 125 (CA-125), which is over expressed in 85% of epithelial OC and it is routinely used to follow response to treatment.1 Complementary to genomics field, new proteomics technologies are under development to identify protein expression, under different physiological conditions: the diagnostic endpoint for OC is not a single biomarker but rather a proteomic pattern, comprising low molecular weight peptides and cleaved proteins.2 Proteomics analysis allows the identification of proteins in response to the treatment. Recently, a new class of pyrroloquinoxaline based compounds with anticancer activity has been identified. The representative example of this series is SN144, a compound selected as a lead, which offers promising pharmacological and pharmacokinetic properties in terms of activity and oral bioavailability. Flow cytometric analysis of DNA profiles shows that SN144 causes cell cycle arrest in the S-phase, this property makes it a potentially ideal agent for combination chemotherapy with agents acting at different stages of cell cycle. Moreover, SN144 induced a clear up-regulation of some proteins implicated in cellular death by apoptosis in treated OC cells. A series of structurally related compounds has been prepared, in order to establish a coherent mode of action and structure-activity relationship. Their peculiar structural feature is the presence of a hydrazine group linking the pyrroloquinoxaline system to an heteroacyl or aminoacyl moiety. The effect of chemical alterations on these analogs are currently under investigation. References 1 J. L. Wilder, E. Pavlik, et al., Gynecol Oncol, 89, 233 (2003). 2 E. F. Petircoin, L. A. Liotta, Molecular Medicine, 10, 2, 59 (2004).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
