Design and synthesis of bridged piperidine and piperazine isosteres.

We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.

Structure-Based Design of a Eukaryote-Selective Antiprotozoal Fluorinated Aminoglycoside.

Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs.

Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT receptor ligands with significant selectivity for D over D receptors.

All clinically-used antipsychotics display similar affinity for both D (D2R) and D (D3R) receptors, and they likewise act as 5-HT receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D and 5-HT (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R.

Toward Overcoming Staphylococcus aureus Aminoglycoside Resistance Mechanisms with a Functionally Designed Neomycin Analogue.

Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50).

Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors.

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors.

SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes.

The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.

Functionalized glycomers as growth inhibitors and inducers of apoptosis in human glioblastoma cells.

The effects of functionalized aryl beta-D-glycopyranosides (glycomers) on the proliferation, survival, and apoptosis of human glioblastoma cells in culture were evaluated as a way to control tumor progression. The results showed that inhibition of growth and/or induction of apoptosis can be achieved by these molecules in human glioblastoma cells. Inhibition of DNA synthesis precedes induction of apoptosis and growth inhibition.

Chemical Synthesis of beta-Homonojirimycin, of Its N-Butyl Derivative, and of "Methyl Homoazacellobioside".

beta-Homonojirimycin (2) was prepared by the highly stereoselective double reductive amination of a 2,6-heptodiulose derivative (6 or 13) using ammonium formate and NaBH(3)CN. The process was unsuccessful with primary amines. The synthesis of N-butyl-beta-homonojirimycin (19) was achieved by the N-butanoylation of a derivative of 2 followed by the reduction of the resulting tertiary amide.