Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of PLK1.

Polo-like kinase 1 (PLK1) is an attractive therapeutic target for the treatment of tumors, as it is an essential cell-cycle regulator frequently overexpressed in tumor tissues. PLK1 can promote tumor invasion and metastasis, and is often associated with poor prognosis in cancer patients. However, no PLK1 inhibitor has been granted marketing approval until now.

9-Cyclopropylmethoxy-dihydrotetrabenazine and its stereoisomers as vesicular monoamine transporter-2 inhibitors.

To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with H-H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays.

LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their cytotoxicity.

The Design, Synthesis and Preliminary Pharmacokinetic Evaluation of d3-Poziotinib Hydrochloride.

To establish a synthetic route to d3-poziotinib hydrochloride. Treatment of 4-chloro-7-hydroxyquinazolin-6-yl pivalate (1) with d3-methyliodide afforded the etherization product, which reacted with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3-4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl pivalate (3). Followed the de-protection reaction, the nucleophilic substitution (S2) reaction with tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (TSP), and the de-protection reaction of t-butoxycarbonyl (Boc) group, and the amide formation reaction with acrylyl chloride, d3-poziotinib was obtained, which was converted to hydrochloride salt by treatment with concentrated hydrochloric acid (HCl).

Synthesis and antitumor activities of 3-substituted-analine derivatives: structure modifications of Tuv part of tubulysins.

Background: Tubulysins family is a kind of natural compound with potent, antitumor activity. To simplify the synthesis route and find new antitumor compounds is becoming a hotspot of research recent years.

Results: Starting from 3-nitrobenzoic acid, after 7 steps transformations, 12 new tubulysin analogues were synthesized by the conformational restraint and bioisostere principle.

Small Molecules as SIRT Modulators.

Sirtuins are a family of NAD+-dependent deacetylases (class III histone deacetylases). Seven mammalian sirtuins, SIRT1-7, are identified, as the functions and locations differ greatly. SIRT1 and SIRT2 locate in nucleus and cytoplasm, while SIRT3-5 in mitochondria.

A concise synthesis of Fingolimod: an orally available drug for treating multiple sclerosis.

A concise route for the synthesis of Fingolimod is reported. Starting from n-octylbenzene and 3-nitropropionic acid, a sequence of reactions consisting of Friedel-Crafts acylation, reduction, and double Henry reaction, followed by hydrogenation were applied to prepare Fingolimod with a yield of 31%, and an overall atom economy of 82.7%.