Evaluation Of Thieno Research Articles

Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors

The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2-d]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-d]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure–activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.

Design, Synthesis, and In vitro Evaluation of Thieno[a]dibenzothiophene Derivatives

AbstractA variety of highly substituted thieno[2,3‐a]dibenzothiophenes and thieno[3,2‐a]dibenzothiophenes are readily prepared via cascade electrophilic cyclization reaction. The reaction was tolerated a variety of compounds. In the present study, antimicrobial and antifungal activities were investigated for all synthesized molecules against A. niger ATCC 16404, C. albicans ATCC 10231, S. aureus ATCC 25923 and B. subtilis ATCC 6633, respectively.

Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel FMS inhibitors

Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.

Abstract 4837: Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents

Abstract Microtubules, attractive targets for drug development as anticancer agents, play vital roles in multiple aspects of cellular metabolism. These agents have been successfully used in the clinic for the treatment of various cancers. However, the utility of such agents are often limited by the emergence of tumor resistance due to overexpression of P-glycoprotein and/or âIII-tubulin. Tumor angiogenic mechanisms are important for tumor growth and metastasis are inhibited by antiangiogenic agents (AAs). AAs are usually cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of antiangiogenic agents with antitubulin agents have been particularly successful. Recently, we reported water-soluble tubulin targeting pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidine analogs as antitumor agents, that circumvent drug resistance. These analogs also possess RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. To further explore the activity of these dual RTK/tubulin inhibitors we designed isosteric thieno[2,3-d] pyrimidine and thieno[3,2-d]pyrimidine analogs which increased microtubule depolymerizing potency by 14 to 24-fold (AG95 IC50 = 7.0 ± 2.7 nM, AG370 IC50 = 7.6 ± 2.1 nM) compared with the lead compounds (AG85 IC50 = 96.6 ± 5.3 nM, AG20 IC50 = 183 ± 3.4 nM). Substitution at the 4-anilino position of both these scaffolds were also explored with various moieties to afford the 6-methoxy-tetrahydroquinoline moiety which possess the optimum balance of microtubule depolymerizing activity (AG372 IC50 = 4.3 ± 1.6 nM, AG337 IC50 = 3.4 ± 0.9 nM,) and RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. These two compounds demonstrated excellent inhibition for EGFR (IC50 = 12.6 ± 1.2 nM, 28.5 ± 3.9 nM), VEGFR-2 (25.2 ± 7.2 nM, 216.1 ± 18.6 nM) and PDGFRâ (IC50 = 25.6 ± 7.2 nM, 266.8 ± 35.4 nM) comparable to the standard clinically used agents. These attributes of the 4-N-substituted thieno pyrimidines provides the impetus for further development of these compounds as dual acting targeted antitumor agents. Citation Format: Aleem Gangjee, Farhana Islam, Tasdique Mohammad Quadery, Susan L. Mooberry, Anja Bastian, Michael A. Ihnat. Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4837.

Correction: Synthesis and evaluation of thieno[2,3-d]pyrimidin-4(3H)-ones as potential antitubercular agents

Correction for ‘Synthesis and evaluation of thieno[2,3-d]pyrimidin-4(3H)-ones as potential antitubercular agents’ by Hanumant B. Borate et al., Med. Chem. Commun., 2015, DOI: 10.1039/c5md00404g.

Synthesis and evaluation of thieno[2,3-d]pyrimidin-4(3H)-ones as potential antitubercular agents

Thieno[2,3-d]pyrimidin-4(3H)-ones with structures 11–38 were synthesized and some of them were found to be potent inhibitors of Mycobacterium tuberculosis H37Ra and/or Mycobacterium bovis BCG and non-toxic to human cell lines.

Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase

Cancer cells have distinct metabolic needs that are different from normal cells and can be exploited for development of anti-cancer therapeutics. Activation of the tumor specific M2 form of pyruvate kinase (PKM2) is a potential strategy for returning cancer cells to a metabolic state characteristic of normal cells. Here, we describe activators of PKM2 based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold. The synthesis of these agents, structure–activity relationships, analysis of activity at related targets (PKM1, PKR and PKL) and examination of aqueous solubility are investigated. These agents represent the second reported chemotype for activation of PKM2.