This paper reports the design and the synthesis of a new family of compounds, the phostines, belonging to the [1,2]oxaphosphinane family. Twenty-six compounds have been screened for their antiproliferative activity against a large panel of NCI cancer cell lines. Because of its easy synthesis and low EC(50) value (500 nM against the C6 rat glioma cell line), compound 3.1a was selected for further biological study. Moreover, the specific biological effect of 3.1a on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, 3.1a has a higher antiproliferative activity than Temozolomide and is more potent than paclitaxel for the SF295 and SNB75 cell lines. In constrast with paclitaxel and vincristine, 3.1a is devoid of astrocyte toxicity. The original activity spectrum of 3.1a on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives.

Keywords: Heterocycles / Bromopyrazoles / Carboxylation / Hydrogen/metal exchange / Halogen/metal exchange / Organolithium intermediatesModern organometallic methods enable the regioflexible conversion of simple heterocyclic starting materials into families of isomers and congeners. Depending on the choice of the reagent, 1-methyl-5-(trifluoromethyl)pyrazole (1) undergoes deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached methyl group. Similarly, 1-phenyl-5-(trifluoromethyl)pyrazole (5) and 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole (8) are selectively attacked by lithium diisopropylamide at the heterocyclic 4-position and by butyllithium concomitantly at the 4-position and the ortho position Efficacy and versatility make organometallic methods particularly suitable for the functionalization of olefinic, aromatic and heterocyclic core structures. [1Ϫ2] The metalation of pyrazole, N-alkylpyrazoles and N-phenylpyrazole at the 5-position has been repeatedly reported. [3Ϫ10] The trapping products qualify as valuable intermediates for the synthesis of pharmaceuticals and agrochemicals. To probe further the intriguing steric and electronic properties of the CF 3 group, [11Ϫ12] we have turned our attention to trifluoromethyl-substituted pyrazoles. Previously, 5-methyl-1-phenyl-3-(trifluoromethyl)pyrazole, 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole and 1-phenyl-3,4-bis(trifluoromethyl)pyrazole have been treated with butyllithium, and metalation at the 4-position of the azole ring has been achieved to the extent of 0%, 11% and 95%, respectively. [13] Under similar conditions, 3-chloro-1-methyl-5-(trifluoromethyl)pyrazole was found to undergo 4-lithiation and subsequent carboxylation in 75% yield. [14] Although (trifluoromethyl)pyrazoles are readily accessible by condensation [15Ϫ27] or [3 ϩ 2] cycloaddition [28] reactions, only one out of eight model substrates studied, 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole, [29] could be prepared according to a literature procedure. The isolation of 1-methyl-5-(trifluoromethyl)pyrazole (1) in 76% yield has also been reported. However, these results were not reproducible. In reality, 4-ethoxy-1,1,1-trifluoro-3-butene-2-one [a] 2913 of the phenyl ring. In contrast, metalation of 1-methyl-3-(trifluoromethyl)pyrazole (2) occurs only at the 5-position, whatever the organometallic or metal amide base. Further sites become accessible to functionalization if bromine is introduced into the heterocyclic or aromatic ring. This has been demonstrated with 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole (3), 4-bromo-1-methyl-3-(trifluoromethyl)pyrazole (4), 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole (7) and 1-(2-bromophenyl)-5-(trifluoromethyl)pyrazole (6). and methylhydrazine afforded a 3:7 mixture (up to 98%) of pyrazole 1 and the regioisomeric 1-methyl-3-(trifluoromethyl)pyrazole (2). A convenient separation of the two components could be accomplished after short reaction times when 4,5-dihydro-...

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Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate, and phosphinate moieties were synthesized. Prepared compounds were evaluated in an enzymatic CDK9/CycT1 assay. The most potent molecules were tested in cell-based toxicity and HIV proliferation assays. Selectivity of shortlisted compounds against CDKs and other kinases was tested. The best compound was shown to be a highly specific, ATP-competitive inhibitor of CDK9/CycT1 with antiviral activity.

Methyl 3‐methoxy‐2‐trifluoromethylacrylate 1, readily prepared by Wittig reaction from methyl 3,3,3‐trifluoropyruvate, has been treated with a number of aryl‐ (or hetaryl‐) hydrazines. Under mild base‐catalysis, the resulting 3‐hydrazinoacrylates 6 undergo consecutive hydrogen fluoride elimination and intramolecular nucleophilic addition to afford methyl 1‐(het)aryl‐5‐fluoropyrazole‐4‐carboxylates 7. 5‐Aminopyrazoles 8 have been obtained by direct reaction of the ester 7a with a lithium amide, whereas 5‐fluoro‐1‐phenylpyrazole‐4‐carboxamides 10 have been formed by condensation of the 5‐fluoro‐1‐phenylpyrazole‐4‐carboxylic acid 9 with amines.

This review first outlines general considerations on phosphinic acids and derivatives as bioisosteric groups. The next sections present key aspects of phosphinic acid-based molecules and include a brief description of the biological pathways involved for their activities. The synthetic aspects and the biological activities of such compounds reported in the literature between 2008 and 2013 are also described.

A highly convergent synthesis of bis(triazolylphosphane oxides) was developed by a tandem copper-mediated Huisgen reaction-oxidative coupling. The phosphane oxides were reduced by trichlorosilane and the coordination of the resulting bisphosphanes was studied with various transition metals.

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