Diversifying Arena of Drug Synthesis: In the Realm of Lipase Mediated Waves of Biocatalysis

Hydrolases, being most prominent enzymes used in industrial processes have left no stone unturned in fascinating the pharmaceutical industry. Lipases, being a part of acyl hydrolases are the ones that function similarly to esterases (except an interfacial action) wherein they generally catalyze the hydrolysis of ester bonds. Be it in terms of stereoselectivity or regioselectivity, lipases have manifested their promiscuous proficiency in rendering biocatalytic drug synthesis and intermediates thereof. Industrial utilization of lipases is prevalent since decades ago, but their distinctive catalytic competencies have rendered them suitable for maneuverability in various tides of biocatalytic industrial process development. Numbers of exquisite catalysts have been fabricated out of lipases using nanobiotechnology whereby enzyme reusability and robustness have been conferred to many of the organic synthesis procedures. This marks a considerable achievement of lipases in the second wave of biocatalysis. Furthermore, in the third wave an advent of genetic engineering has fostered an era of customized lipases for suitable needs. Be it stability or an enhanced efficacy, genetic engineering techniques have ushered an avenue for biocatalytic development of drugs and drug intermediates through greener processes using lipases. Even in the forthcoming concept of co-modular catalytic systems, lipases may be the frontiers because of their astonishing capability to act along with other enzymes. The concept may render feasibility in the development of cascade reactions in organic synthesis. An upcoming wave demands fulfilling the vision of tailored lipase whilst a far-flung exploration needs to be unveiled for various research impediments in rendering lipase as a custom fit biocatalyst in pharmaceutical industry.

Ultra-fast Cu-based A3-coupling catalysts: faceted Cu2O microcrystals as efficient catalyst-delivery systems in batch and flow conditions

Cu(I) catalysts were studied for the synthesis of a propargylamine via A3-coupling of aldehyde, amine, and alkyne, under solvent-free and low loading conditions, using batch microwave or flow thermal heating. We explore ultra-low loading conditions with Cu(I) salts as ultra fast and active catalysts featuring TOFs above 105 h-1. Well-defined octahedral and cubic Cu2O microcrystals were also successfully applied and compared to this reaction. Both types of microcrystals exhibited excellent catalytic activities within minutes, via in-situ generation of low dose of Cu(I) ions within the reaction medium, to achieve TON beyond 2000 and recycling up to 10 times in a flow reactor. The study of the catalytic system demonstrated that the activity was surface-structure dependent and allowed for the design of low Cu contamination A3-coupling systems, affording a product at the decigram scale, with Cu contamination below FDA recommendations for drug synthesis, without the need for a purification procedure.

Biologically oriented synthesis of medicines (BIODS) based on heterylpoxid 2,5-disubstituted 1,3,4-oxadiazoles (Part 2)

Heterocyclic compounds make a very important branch of organic chemistry, and it has always been an interesting area of study in medical chemistry. They are present in a variety of drugs, vitamins and biologically active compounds. Over two decades, 1,3,4-oxadiazoles have been of interest to chemists owing to their diverse therapeutic potential; the studies focus mainly on the principles of combinatorial chemistry with a broad spectrum of biological activity. In the continuation of the review article, the general literature sources that consider chemical heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazoles as important synthetic substrates and precursors for biologically oriented synthesis, are systematized. Heterocyclic 1,3,4-oxadiazoles and their derivatives are widely used as antibacterial, fungicidal, anti-inflammatory, antidiabetic, anticancer, antitubercular, antioxidant, antimalarial, analgesic, anticonvulsant, antidepressant and anti-HIV drugs. It is important to note that the combination of 1,3,4-oxadiazole nuclei with different heterocyclic moieties in some cases had synergistic effect. The aim of the work is the search for new activities, systematization and generalization of literature sources on methods of biologically oriented drug synthesis (BIODS) based on heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazoles. Conclusions. The article analyzes, generalizes and systematizes the data obtained from the literature that describes the results of the study of the biological activity of 1,3,4-oxadiazoles, which allowed to confirm their diverse pharmacological and biological potential. It is established that oxadiazoscafold as the main structural component is found in various biologically active compounds which evidences the relevance of its further studies as a perspective structural matrix for construction of drug-like molecules. The analysis of the presented material demonstrates the significance and prospectivity of biologically oriented drugs of this segment of the chemistry of nitrogen-containing heterocycles.

Structure-guided protein engineering of ammonia lyase for efficient synthesis of sterically bulky unnatural amino acids

Enzymatic asymmetric amination addition is seen as a promising approach for synthesizing amine derivatives, especially unnatural amino acids, which are valuable precursors to fine chemicals and drugs. Despite the broad substrate spectrum of methylaspartate lyase (MAL), some bulky substrates, such as caffeic acid, cannot be effectively accepted. Herein, we report a group of variants structurally derived from Escherichia coli O157:H7 MAL (EcMAL). A combined mutagenesis strategy was used to simultaneously redesign the key residues of the entrance tunnel and binding pocket to explore the possibility of accepting bulky substrates with potential application to chiral drug synthesis. Libraries of residues capable of lining the active center of EcMAL were then constructed and screened by an effective activity solid-phase color screening method using tyrosinase as a cascade catalyst system. Activity assays and molecular dynamics studies of the resultant variants showed that the substrate specificity of EcMAL was modified by adjusting the polarity of the binding pocket and the degree of flexibility of the entrance tunnel. Compared to M3, the optimal variant M8 was obtained with a 15-fold increase in catalytic activity. This structure-based protein engineering of EcMAL can be used to open new application directions or to develop practical multi-enzymatic processes for the production of various useful compounds.