pyrrolopyrimidine 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

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Male; Mice; Mice, Nude; Mice, SCID; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Signal Transduction; Xenograft Model Antitumor Assays

A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d]pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts.. Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3Kα related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Kα inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3).. Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4- aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase.

Topics: Amination; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; Male; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostate; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles

Previously, we synthesized a new carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside, designated MCS-C3. Recently, we found that LNCaP androgen-responsive prostate cancer cells treated with MCS-C3 rapidly undergo intrinsic apoptosis through dramatic up-regulation of p21(CIP1). The present study aimed to evaluate the cellular functions and underlying molecular mechanisms of p21(CIP1) on apoptotic induction in LNCaP cells treated with 6 μM MCS-C3.. Western blots, flow cytometric assay, immunoprecipitation, and transmission electron microscopy analysis were used to measure apoptotic induction in 6-μM MCS-C3-treated LNCaP cells. Effects of MCS-C3 on gene expression of p21(CIP1) were measured by semi-quantitative real-time polymerase chain reaction, and small interfering RNA transfection.. MCS-C3 induced appreciable caspase-dependent apoptosis associated with the significant up-regulation of p53-dependent p21(CIP1) in LNCaP cells. Moreover, this apoptotic induction was caused by direct binding of p21(CIP1) to anti-apoptotic B-cell lymphoma 2 (BCL2) protein, and antagonizing BCL2 function. In addition, MCS-C3-mediated apoptotic induction, and up-regulation of p21(CIP1) were almost completely blocked by the treatment of androgen-responsive LNCaP cells with flutamide, an androgen receptor (AR) antagonist.. We identified that induction of intrinsic apoptosis in LNCaP cells by 6 μM MCS-C3 is associated not only with p53 activation but also with mediation of AR. In the present study, we identified the cellular functions and underlying molecular mechanisms of p53-dependent and AR-associated p21(CIP1) on apoptotic induction via direct binding to BCL2 in LNCaP cells treated with 6 μM MCS-C3.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Pyrroles; Signal Transduction; Transfection