Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs

Abstract

Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the largest selling class of drugs prescribed for the pharmacological treatment of hypercholesterolemia and dyslipidaemia. Statins also possess other therapeutic effects, called pleiotropic, because the blockade of the conversion of HMG-CoA to (R)-mevalonate produces a concomitant inhibition of the biosynthesis of numerous isoprenoid metabolites (e.g., geranylgeranyl pyrophosphate (GGPP) or farnesyl pyrophosphate (FPP)). Thus, the prenylation of several cell signalling proteins (small GTPase family members: Ras, Rac, and Rho) is hampered, so that these molecular switches, controlling multiple pathways and cell functions (maintenance of cell shape, motility, factor secretion, differentiation, and proliferation) are regulated, leading to beneficial effects in cardiovascular health, regulation of the immune system, anti-inflammatory and immunosuppressive properties, prevention and treatment of sepsis, treatment of autoimmune diseases, osteoporosis, kidney and neurological disorders, or even in cancer therapy. Thus, there is a growing interest in developing more sustainable protocols for preparation of statins, and the introduction of biocatalyzed steps into the synthetic pathways is highly advantageous-synthetic routes are conducted under mild reaction conditions, at ambient temperature, and can use water as a reaction medium in many cases. Furthermore, their high selectivity avoids the need for functional group activation and protection/deprotection steps usually required in traditional organic synthesis. Therefore, biocatalysis provides shorter processes, produces less waste, and reduces manufacturing costs and environmental impact. In this review, we will comment on the pleiotropic effects of statins and will illustrate some biotransformations nowadays implemented for statin synthesis.

A Glimpse into Green Chemistry Practices in the Pharmaceutical Industry

“…Key features of this technology include the use of water as green reaction media, better selectivity, and no product contamination by trace metals . Besides, it does not require any protection/deprotection steps, and it is generally highly enantioselective and can be performed under mild conditions . Enzymes, a key component in biocatalysis, have been employed successfully in many key transformations, such as reduction, hydroxylation, oxidation, hydrolysis, and some other useful transformations .…”

The Hitchhiker's guide to biocatalysis: recent advances in the use of enzymes in organic synthesis

“…The high specicity of enzymes obviates the need for protection and deprotection steps. 62 Examples of the successful integration of biocatalysis steps into a traditional synthetic process are many, including diltiazem, 186 sitagliptin, 173 pregabalin, 89 atorvastatin 104,187 and other statins, 188 to name but a few.…”

Biocatalysis explained: from pharmaceutical to bulk chemical production

“…The overall process needs six steps which are technically and economically demanding. 27 On the other hand, the biocatalytic approach towards simvastatin requires just two steps (Scheme 8). With the development of a whole cell acyltransferase LovD which enables the regioselective acylation of the C-8 hydroxyl group of monacolin J with α-dimethylbutyryl-S-N-acetylcysteamine (DMB-S-NAC), simvastatin is afforded directly.…”

“…35 This three-enzyme, two-step process has been successfully carried out on a multiton scale by Codexis. 27 Several processes that use NADIJP) + -dependent alcohol dehydrogenases (ADHs) for the enantio-specific reduction of carbonyl groups have been proposed in the literature. 18,36 In particular, the application of ADHs is more fascinating when used in a redox neutral environment, in combination with hydroxylating enzymes (cytochrome P450), 37 reductive aminases 38 or stereocomplementary ADHs.…”