cgp-77675 and Prostatic-Neoplasms

Fused heterocycles are reported to demonstrate variety of biological activities such as anticancer, antibacterial, antifungal and anti-inflammatory, and are thus exhaustively utilized in the field of medicinal chemistry. Pyrrolopyrimidines is one of the major classes of fused heterocycles which are extensively reported throughout the literature. Several reports suggest that pyrrolopyrimidine as fused scaffold possess more diverse and potent pharmacological profile than individual pyrrole and pyrimidine nucleus. Different pathological targets require different structural attributes reflected via varied substitutions, thus in recent years, researchers have employed various synthetic strategies to achieve desired substitutions on the pyrrolopyrimidine nucleus. In this review, authors highlight the recent advancement in this area, special focus was laid on the pharmacological profile and structure-activity relationship studies (SAR) of various synthesized pyrrolopyrimidine derivatives.

Topics: Animals; Anti-Retroviral Agents; Antineoplastic Agents; HIV Infections; Humans; Male; Molecular Structure; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Pyrimidines; Pyrroles; Structure-Activity Relationship

Two bona fide c-Src inhibitors, denominated CGP77675 and CGP76030, reduced in a time- and concentration-dependent manner (i) the proliferation of the PC3 prostate carcinoma cell line, as assessed by the [3H]-thymidine incorporation test, (ii) the capacity of PC3 cells to adhere and spread on Matrigel substrate, as determined by crystal violet staining, (iii) the ability of PC3 cells to migrate through a gelatine boundary and invade a Matrigel substrate. The latter effect was not due to a decrease of urokinase-type plasminogen activator (uPA), nor of metalloproteinase-2 (MMP-2) activities. The MMP-9 activity, along with the expression of the Tissue Inhibitor of Metalloproteinases (TIMP)-1 and TIMP-2, were reduced by the two inhibitors, consistent with the ability of c-Src to enhance MMP-9 and TIMP expression levels. Collectively, these data demonstrate that the pyrrolopyrimidine-derived c-Src inhibitors significantly reduced PC3 cell activities associated with their malignant phenotype.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Adhesion; Cell Division; Cell Movement; Cell Size; CSK Tyrosine-Protein Kinase; Drug Screening Assays, Antitumor; Humans; Male; Matrix Metalloproteinases; Neoplasm Invasiveness; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; src-Family Kinases; Tumor Cells, Cultured