Facile Synthesis of Cyclohexanediones and Dialkylresorcinols – Bioactive Natural Products from Entomopathogenic Bacteria

Abstract

A synthesis for the recently identified, widespread bacterial natural product classes of dialkylresorcinols and cyclohexanediones was developed. The synthesis route is similar to the biosynthesis route in that the formation of the cyclohexanedione ring results from two parts, as exemplified by the synthesis of the multifunctional isopropylstilbenes identified in Photorhabdus luminescens. Testing of these compounds revealed good bioactivity against Trypanosoma brucei rhodesiense and T. cruzi, the causative agents of sleeping sickness and Chagas disease, respectively.

Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease

“…Our results demonstrate that the annotated coding sequence of TcSir2rp1 encodes for an essential (as genetically validated here) canonical sirtuin that does not display deacetylation activity in the absence of NAD + and is mostly insensitive to TSA. Kinetic data obtained for TcSir2rp1 is highly similar to the values previously described for TbSir2rp1 [ 67 ]. Despite moderate differences in primary sequence (61%), a close analysis of the amino acids adjacent to the essential histidine (H142) at the catalytic site demonstrates a 100% similarity of the four amino acids upstream and downstream, which likely participate and/or help shape the catalytic site, and thus may explain the similarity observed.…”

“…The steady-state kinetic parameters ( K m, V max , k cat and k cat / K m values) of deacetylase activity were determined ( Table 1 ). By way of confirmation, the same kinetic parameters were also independently assessed using an electrophoretic mobility shift assay, performed as described previously [ 67 ]. Highly similar values (Km’s of 38.7 ± 1.5 μM for NAD + and 32.3 ± 6.0 μM for substrate (TSPQPKK-Ac)) were obtained using the alternative microfluidic based assay confirming that the two different techniques generated essentially similar results when used to assess TcSir2rp1 NAD + -dependent deacetylase activity.…”

Biocatalytic Friedel–Crafts Alkylation Using a Promiscuous Biosynthetic Enzyme

“…[18] Current methods to access 6 require at least five steps and rely on harsh conditions, with methoxy protecting groups on the resorcinol moiety. [19][20][21] In particular, the process route to 6 involves a Friedel-Crafts reaction that limits the alkyl substituent to the symmetric isopropyl group. [19] Larger and/or asymmetric secondary alkyl groups could not be accessed via this route due to the generation of carbocationic intermediates that hinder regio-and stereospecificity.…”

Chemistry, bioactivity and biosynthesis of cyanobacterial alkylresorcinols

“…Effective synthetic routes to simple natural DARs have been designed 81,82. In these studies, alkylated α,β-unsaturated ketones and diethylmalonate were subjected to Michael addition/Dieckmann condensation followed by saponification/decarboxylation to generate alkylcyclohexane-1,3-diones.…”