Fermentation Simvastatin

Subsequently, a second, closely related molecule—lovastatin—was discovered by scientists at Merck in the United States in another fungal fermentation broth and by Sankyo in Japan. Lovastatin, marketed as Mevacor in the United States, proved both safe and efficacious for the intended nse and was the first statin to be approved for human use. Several others, some mentioned above, followed. The history of discovery and development of HMGR inhibitors has been pnUed together by Jonathan Tobert, who led the lovastatin and simvastatin clinical development effort at Merck. ... 

The high-value HMG-CoA reductase inhibitor Simvastatin (8) is marketed by Merck under the name Zocor. The active ingredient is obtained from a fermentation approach. It is very similar in structure to lovastatin, which has fallen from the top-sellers list. Lovastatin (9) is also a cholesterol-reducing drug that is isolated from Aspergillus terreus.51-60 It is still obtained by fermentation,61 and with the current advances in molecular biology,62 64 chemical approaches are not able to compete in a cost-effective manner.65-67 The usage of lipases allows for the manipulation of the butyric acid sidechain to access other HMG-CoA reductase inhibitors such as simvastatin.68 A number of routes to various portions of lovastatin have been reported.69... 

As mentioned, fermentation is used to provide the core structure of simvastatin, and hydrolysis is used to remove the 2-methylbutyrate sidechain the dimethylbutyric acid sidechain is introduced by coupling (Scheme 31.6).70-73 Chemical methylation to form the quaternary dimethylated center in the sidechain has been achieved on synthetic intermediates.7475 The chemical approach has to differentiate two hydroxy groups, and this requires protection-deprotection steps.76-86... 

Pravastatin (10) is another HMG-CoA reductase for the inhibition of cholesterol biosynthesis it is marketed by Sanyo and Bristol Myers Squibb under the trade names Mevalotin and Pravachol.87 It has a close structural relationship to lovastatin and simvastatin. It is produced by a two-step sequence. First, mevastatin (11), also known as ML-236B or compactin, is prepared by fermentation of Penicillium citrinum ss it is then enzymatically hydroxylated to produce 11 (Scheme 31.7).88-101... 

Fermentation has produced natural products such as antibiotics and the cholesterollowering agents pravastatin and lovastatin. Modification of fermentation products has led to semisynthetic compounds such as simvastatin (see Figure 1.2), penicillins, and cephalosporins. With increased capability in genetic engineering,... 

Statins can be classified as natural statins and synthetic statins. Lavastatin, simvastatin, and pravastatin are the first three natural statins to reach the market. Lavastatin and pravastatin are natural products isolated from fermentation broths, while simvastatin is a semisynthetic statin derived from lavastatin. Fluvastin was the first truly synthetic statin brought to the market by Sandoz pharmaceutical company (now part of Novartis), and it was obtained by replacing the hexahydro-naphthalene core stiucture of the natural statins with the indole nucleus [5]. It was the discovery of fluvastin that opened up the opportunity of more potent synthetic statins including atorvastatin, the most prescribed drug in the world. 

Shine-Dalgarno (SD) sequence 588 signal peptidase (SPase) 225 signal peptides 225 simultaneous saccharification and fermentation (SSF) process 681 simvastatin 523... 

In spite of a multitude of total syntheses of statins, those which occur naturally are obtained on an industrial scale by fermentation, and in the case of simvastatin, by partial synthesis. Only those statins containing a nitrogen heterocycle are obtained by total syntheses. [391] Hereafter, selected representative examples are presented. 

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

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