An operationally simple and high-yielding procedure has been developed for the conversion of primary amides to the corresponding nitriles, using ethyl dichlorophosphate/DBU as the mild dehydrating agent.

Motivated by the pivotal role of CXCR4 as an HIV entry coreceptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4+/CD34+ stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.

Silent biosynthetic gene clusters represent a potentially rich source of new bioactive compounds. We report the discovery, characterization, and biosynthesis of a novel doubly glycosylated 24-membered polyene macrolactam from a silent biosynthetic gene cluster in Streptomyces roseosporus by using the CRISPR-Cas9 gene cluster activation strategy. Structural characterization of this polyketide, named auroramycin, revealed a rare isobutyrylmalonyl extender unit and a unique pair of amino sugars. Relative and absolute stereochemistry were determined by using a combination of spectroscopic analyses, chemical derivatization, and computational analysis. The activated gene cluster for auroramycin production was also verified by transcriptional analyses and gene deletions. Finally, auroramycin exhibited potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity towards clinical drug-resistant isolates.

A novel class of (5-(pent-1-enyl)thiophen-2-yl)pyrazole antagonists was discovered, many of which exhibited potent CB1 activity and good CB1/2 selectivity, suggesting that along with a 1,3-transposition of the carbonyl of the pyrazole 3-carboxamide, bioisosteric replacement of the conventional pyrazole 5-aryl group with a thienyl ring substituted with an appropriate alkenyl moiety is viable.

Polyene cyclization of compounds 3 and 4 under catalysis with AlCl3 and/or SnCl4 gave rise to complex bicyclic products 8 and 9, structures of which were highly unexpected, and X-ray analyses were invoked for unambiguously structural identification. Mechanistically, a tandem sigma-bond rearrangement process, including an unusual through-space 1,5-hydride or 1,3-alkyl shift as a key operation, is proposed.