Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent

Abstract

We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4'-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC values for antiproliferative effects in MDA-MB-435 melanoma cells. Particularly, the S-methyl analog 3 was more potent than 1 in MDA-MB-435 cells (IC = 4.6 nM). Incubation of 3 with human liver microsomes showed that the primary metabolite of the S-methyl moiety of 3 was the methyl sulfinyl group, as in analog 5. This metabolite was equipotent with the lead compound 1 in MDA-MB-435 cells (IC = 7.9 nM). Molecular modeling and electrostatic surface area were determined to explain the activities of the analogs. Most of the potent compounds overcome multiple mechanisms of drug resistance and compound 3 emerged as the lead compound for further SAR and preclinical development.

Synthesis and Pharmacological Evaluation of Noncatechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists

“…Coupling of 32 with the corresponding heterocyclic halides under the C−N conditions produced compounds 33 and 34, respectively.Compounds 42 and 43 were designed by adding a methyl group to compounds 33 and 34, respectively, and the synthetic procedures are outlined in Scheme 3. 4-Methylindoline(36) was obtained by hydrogenation of the starting material 4methyl-1H-indole(35).Protection of intermediate 36 by CbzCl in the presence of Et 3 N led to intermediate 37. Compound 38 was prepared by reacting intermediate 37 with NBS.…”

“…Deprotection of the benzyl group of 17 led to intermediate 18 . Compounds 19 – 24 were obtained by reaction of intermediate 18 with the corresponding heterocyclic halides − in the presence of Cs 2 CO 3 , followed by deprotection of the 2-(trimethylsilyl)ethoxymethyl group.…”

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

“… Isosteric replacement: To explore the activities of compounds with the 4,5,6,7-tetrahydrobenzo thiophene scaffold on both inhibition of cancer cell proliferation and microtubule depolymerization, we carried out the isosteric replacement of the scaffold -NH- of the lead compounds 1 – 3 by sulfur (-S-) to afford target compounds 4 – 14 ( Table 1 ). Isosteric replacement of -NH with (-S-) has literature precedence in improving antiproliferative and microtubule depolymerizing activities [ 27 ]. Moreover, pharmacological applications of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidines have been extensively illustrated in various reports in the literature [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

Functionalization of the C20 fullerene by pyridine and pyrimidine: A theoretical study

“…Pyridine and pyrimidine are two basic heterocyclic compounds, which occur naturally within the structure of vitamins and natural products [20,21]. They also exist in the structure of many pharmaceutical agents such as antibacterial, antiviral, antioxidant, antidiabetic, anticancer, antimalarial and anti-inflammatory drugs [22][23][24].…”