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Thieno[3,2-d]pyrimidine ring framework comprises a significant class of heterocyclics that serve as a promising platform showing different pharmacological activities. The interest in thieno[3,2-d]pyrimidine cores for pharmaceutical products makes this scaffold an exceptionally helpful building block for organic chemistry. This review presents current research on thieno[3,2- d]pyrimidines and elucidates their biological importance in anti-cancer, anti-infectious, anticonvulsant, anti-diabetic, CNS, and osteoporosis drug discoveries. Patents on the thieno[3,2- d]pyrimidines are also elaborated as a piece of useful information. Here, we additionally focus on the synthesis of this vital ring and the discovery of new thieno[3,2-d]pyrimidines.

The design, synthesis, and biological evaluation of a series novel N1‑methyl pyrazolo[4,3-d]pyrimidines as inhibitors of tubulin polymerization and colchicine binding were described here. Synthesis of target compounds involved alkylation of the pyrazolo scaffold, which afforded two regioisomers. These were separated, characterized and identified with (1)H NMR and NOESY spectroscopy. All compounds, except 10, inhibited [(3)H] colchicine binding to tubulin, and the potent inhibition was similar to that obtained with CA-4. Compounds 9 and 11–13 strongly inhibited the polymerization of tubulin, with IC(50) values of 0.45, 0.42, 0.49 and 0.42 μM, respectively. Compounds 14–16 inhibited the polymerization of tubulin with IC(50s) near ~1 μM. Compounds 9 12, 13 and 16 inhibited MCF-7 breast cancer cell lines and circumvented βIII-tubulin mediated cancer cell resistance to taxanes and other MTAs, and compounds 9–17 circumvented Pgp-mediated drug resistance. In the standard NCI testing protocol, compound 9 exhibited excellent potency with low to sub nanomolar GI(50) values (≤10 nM) against most tumor cell lines, including several multidrug resistant phenotypes. Compound 9 was significantly (P

A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

A series of methoxy naphthyl substituted cyclopenta[d]pyrimidine compounds, 4–10, were designed and synthesized to study the influence of the 3-D conformation on microtubule depolymerizing and antiproliferative activities. NOESY studies with the N,2-dimethyl-N-(6ʹ-methoxynaphthyl-1ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (4) showed hindered rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. In contrast, NOESY studies with N,2-dimethyl-N-(5ʹ-methoxynaphthyl-2ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (5) showed free rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. The rotational flexibility and conformational dissimilarity between 4 and 5 led to a significant difference in biological activities. Compound 4 is inactive while 5 is the most potent in this series with potent microtubule depolymerizing effects and low nanomolar IC(50) values in vitro against a variety of cancer cell lines. The ability of 5 to inhibit tumor growth in vivo was investigated in a U251 glioma xenograft model. The results show that 5 had better antitumor effects than the positive control temozolomide and has identified 5 as a potential preclinical candidate for further studies. The influence of conformation on the microtubule depolymerizing and antitumor activity forms the basis for the development of conformation-activity relationships for the cyclopenta[d]pyrimidine class of microtubule targeting agents.

Microtubules are cytoskeleton protein polymers composed of αß-tubulin heterodimers which play pivotal roles in cell division, cellular transport and cell signaling. Interfering with microtubule dynamics is a well-established strategy for the treatment of cancer. However, clinical utility of microtubule targeting agents (MTAs) in cancer chemotherapy is often limited by the emergence of drug resistance. Expression of P-glycoprotein (Pgp) or the βIII isotype of tubulin, are two clinically established drug resistance mechanisms. We previously reported that compound AG346 binds to the colchicine site of tubulin and has microtubule depolymerization activity in A-10 cells (EC50 = 365 nM). Molecular modeling and docking studies of this compound in the X-ray crystal structure of tubulin (PDB: 402B) suggested that the pyrrole NH can be substituted with alkyl chains of optimal length to obtain an altered binding conformation which can facilitate interaction with the hydrophobic pocket formed by amino acid Val181 of side chain A, and Lys352 and Thr314 of side chain B. We designed and synthesized a variety of pyrrole NH-alkyl substituted compounds and determined that the compound AG473 shows a 43-fold improved microtubule depolymerization potency (EC50 = 8.4 nM) in A-10 cells, compared to the lead compound. In addition, this compound inhibited the growth of human melanoma cancer cell line MDA-MB-435 in culture with an IC50 of 7.2 nM, which is a 5-fold improvement in potency over the parent compound. These analogs also circumvented resistance mediated by Pgp and βIII-tubulin. These attributes provide the impetus for further preclinical development of these compounds as microtubule targeted antitumor agents in vivo and these studies are currently underway. Citation Format: Aleem Gangjee, Tasdique M. Quadery, Susan L. Mooberry. Structure-activity relationship study of pyrrolo[2,3- d]pyrimidines as microtubule targeting antitumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5105. doi:10.1158/1538-7445.AM2017-5105