Semisynthesis of new D-seco-C-nor-taxane derivatives containing a polyfunctionalized furanosyl or cyclopentenyl or cyclopentyl C-ring.

The synthesis of new D-seco-C-nor-taxane derivatives in which the D-ring has been deleted and the C-ring has been transformed into a new pentatomic ring, i.e., the polyfunctionalized tetrahydrofuranosyl and cyclopentenyl or cyclopentyl ring, was performed starting from baccatin III derivatives. The synthetic strategy adopted took advantage of the oxetane ring opening and disconnection of the C4-C5 bond, followed by an intramolecular condensation. The formation of furanosyl or cyclopentyl rings is strictly dependent on the presence of unprotected or protected oxygen at C-7 in the starting material. The reactions proceeded with good diastereoselectivity with control of the stereochemistry of one or two stereocenters.

SAR and QSAR study on 2-aminothiazole derivatives, modulators of transcriptional repression in Huntington's disease.

REST/NRSF is a multifunctional transcription factor that represses or silences many neuron-specific genes in both neural and non-neural cells by recruitment to its cognate RE1/NRSE regulatory sites. An increase in RE1/NRSE genomic binding is found in Huntington's disease (HD), resulting in the repression of REST/NRSF regulated gene transcription, among which BDNF, thus representing one of the possible detrimental effectors in HD. Three 2-aminothiazole derivatives were recently identified as potent modulators of the RE1/NRSE silencing activity through a cell-based gene reporter assay. In this study, the structure-activity relationships (SAR) of a library of commercially available 2-aminoisothiazoles diversely substituted at the amino group or at position 4 has been evaluated. A quantitative structure-activity relationship analysis performed using the Phase strategy yielded highly predictive 3D-QSAR pharmacophore model for in silico drug screening.

[2 + 4] and [4 + 2] cycloadditions of o-thioquinones with 1,3-dienes: a computational study.

Cycloadditions of o-thioquinones (o-TQs) with 1,3-dienes could proceed via either a [2 + 4] or a [4 + 2] mechanism. Under kinetic control and with acyclic dienes the reaction affords the spiro cycloadducts 5deriving from the [2 + 4] path as the main products. Under thermodynamic control, or with cyclic dienes, the o-TQs behave as heterodienes to give the benzoxathiin derivatives 4, in most cases with complete regioselectivity. In the present computational study, DFT calculations were performed in order to achieve a deep understanding of both [2 + 4] and [4 + 2] paths. The reactions of three o-TQs with six 1,3-dienes were thoroughly investigated at the B3LYP/TZVP//B3LYP6-31G level, and the two reaction mechanisms were then compared, evidencing that [2 + 4] cycloadditions are kinetically favored, strongly asynchronous, or even unconcerted, while [4 + 2] reactions are thermodynamically favored, quite asynchronous, but undoubtedly concerted. Moreover, the observed regioselectivity was rationalized by mean of the FMO theory and by comparison of the activation energies for different pathways.