Project description:Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the 'parent' taxane--taxadiene--which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels-Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.
Project description:Chiral aromatic alcohols have received much attention due to their widespread use in pharmaceutical industries. In the asymmetric synthesis processes, the excellent performance of alcohol dehydrogenase makes it a good choice for biocatalysts. In this study, a novel and robust medium-chain alcohol dehydrogenase RhADH from Rhodococcus R6 was discovered and used to catalyse the asymmetric reduction of aromatic ketones to chiral aromatic alcohols. The reduction of 2-hydroxyacetophenone (2-HAP) to (R)-(-)-1-phenyl-1,2-ethanediol ((R)-PED) was chosen as a template to evaluate its catalytic activity. A specific activity of 110 U mg-1 and a 99% purity of e.e. was achieved in the presence of NADH. An efficient bienzyme-coupled catalytic system (RhADH and formate dehydrogenase, CpFDH) was established using a two-phase strategy (dibutyl phthalate and buffer), which highly raised the tolerated substrate concentration (60 g l-1 ). Besides, a broad range of aromatic ketones were enantioselectively reduced to the corresponding chiral alcohols by this enzyme system with highly enantioselectivity. This system is of the potential to be applied at a commercial scale.
Project description:Enhancing the antibacterial activity of old antibiotics by a multitarget approach, such as combining antibiotics with metal nanoparticles, is a valuable strategy to overcome antibacterial resistance. In this work, the synergistic antimicrobial effect of silver nanoparticles and antibiotics, immobilized on a solid support, was investigated. Nanometric layered double hydroxides (LDH) based on Zn(II) and Al(III) were prepared by the double microemulsion technique. The dual function of LDH as an anionic exchanger and support for metal nanoparticles was exploited to immobilize both silver and antibiotics. Cefazolin (CFZ), a β-lactam, and nalidixic acid (NAL), a quinolone, were selected and intercalated into LDH obtaining ZnAl-CFZ and ZnAl-NAL samples. These samples were used for the growth of silver nanoparticles with dimension ranging from 2.5 to 8 nm. Silver and antibiotics release profiles, from LDH loaded with antibiotics and Ag/antibiotics, were evaluated in two different media: water and phosphate buffer. Interestingly, the release profiles are affected by both the acceptor media and the presence of silver. The synergistic antibacterial activity of LDH containing both silver and antibiotics were investigated on gram-positives (Staphylococcus aureus and Streptococcus pneumoniae) and gram-negatives (Pseudomonas aeruginosa) and compared with the plain antimicrobials and LDH containing only antibiotics or silver.
Project description:The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern1. For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings2. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the [Formula: see text] nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.
Project description:Fusarisetin A (1) is a recently isolated natural product that displays an unprecedented chemical motif and remarkable bioactivities as a potent cancer migration inhibitor. We describe here our studies leading to an efficient and scalable total synthesis of 1. Essential to the strategy was the development of a new route for the formation of a trans-decalin moiety of this compound and the application of an oxidative radical cyclization (ORC) reaction that produces fusarisetin A (1) from equisetin (2) via a bio-inspired process. TEMPO-induced and metal/O(2)-promoted ORC reactions were evaluated. Biological screening in vitro confirms the reported potency of (+)-1. Importantly, ex vivo studies show that this compound is able to inhibit different types of cell migration. Moreover, the C(5) epimer of (+)-1 was also identified as a potent cancer migration inhibitor, while (-)-1 and 2 were found to be significantly less potent. The optimized synthesis is applicable on gram scale and provides a solid platform for analogue synthesis and methodical biological study.
Project description:Antibiotic resistance in the opportunistic pathogen Pseudomonas aeruginosa is partly caused by biofilms forming a physical barrier to antibiotic penetration. Here we focused on modifying tetravalent glycopeptide dendrimer ligands of P. aeruginosa lectins LecB or LecA to increase their biofilm inhibition activity. First heteroglycoclusters were investigated displaying one pair each of LecB specific fucosyl groups and LecA specific galactosyl groups and binding simultaneously to both lectins, one of which gave the first fully resolved crystal structure of a peptide dendrimer as LecB complex providing a structural model for dendrimer-lectin interactions (PDB ; 5D2A). Biofilm inhibition was increased by introducing additional cationic residues in these dendrimers but resulted in bactericidal effects similar to those of non-glycosylated polycationic antimicrobial peptide dendrimers. In a second approach dendrimers displaying four copies of the natural LecB ligand Lewisa were prepared leading to slightly stronger LecB binding and biofilm inhibition. Finally synergistic application of a LecB specific non-bactericidal antibiofilm dendrimer with the antibiotic tobramycin at sub-inhibitory concentrations of both compounds allowed effective biofilm inhibition and dispersal.
Project description:Since the accompanying study had shown that the introduction of the eponymous aldgarose sugar to the C5-OH group of the macrocyclic aglycone of aldgamycin N is most difficult, if not even impossible, the synthesis route was revised and the glycosidation performed at an earlier stage. To mitigate the "cost" of this strategic amendment, a practical and scalable de novo synthesis of this branched octose was developed. The glycoside formation required mild conditions; it commenced with the reaction of the aglycone with the trichloroacetimidate donor to give a transient orthoester, which slowly rearranged to the desired aldgaropyranoside. The presence of the polar peripheral groups in the product did not impede the selective late-stage functionalization of the macrolide ring itself: the contained propargylic alcohol entity was readily transformed into the characteristic acyloin motif of the target by a ruthenium-catalyzed trans-hydrostannation followed by a modified Chan-Lam-type coupling.
Project description:Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.
Project description:A total synthesis of ammosamide B, a metabolite of the marine-derived Streptomyces strain CNR-698, has been executed in nine steps and 6.9% overall yield. The key step involves the condensation of a 4,6-diBoc-protected 1,3,4,6-tetraaminobenzene derivative with dimethyl 2-ketoglutaconate, which effectively constructs the pyrrolidinone ring and the quinoline ring in a single step. This contributes a unique approach to the synthesis of pyrroloquinoline alkaloids that offers the advantages of brevity and relatively high overall yield.
Project description:There is an urgent need to discover new drugs to address the pressing problem of antibiotic-resistance. Macrolide antibiotics such as erythromycin (1) are safe, broad-spectrum antibiotics used in the clinic since 1954. Herein we report the synthesis and evaluation of 4,8,10-tridesmethyl telithromycin (3), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2), which is a semisynthetic derivative of 1. Analogue 3 was found to possess antibiotic activity and was superior to telithromycin (2) when tested against resistant strains of S. aureus possessing an A→T mutation at position 2058 (E. coli numbering).