Fermentative syntheses inhibitors

Lee CH, Chung MC, Lee HJ, Bae KS, Kho YH (1997) MR566A and MR566B, New Melanin Synthesis Inhibitors Produced by Trichoderma harzianum I. Taxonomy, Fermentation, Isolation and Biological Activities. J Antibiot 50 469... 

Low-molecular-weight inhibitors, on the other hand, probably could be obtained in large amounts either by synthesis or fermentation. In most cases they would be likely to be orally active. In addition, it would be feasible to carry out structural modifications on the inhibitor to increase reactivity and selectivity or to reduce toxicity. 

Numerous biotranformation processes for fhe synthesis of amino acids have been described and for fhe purpose of this chapter, we have restricted the discussion to fhe unnatural amino acids fhat are not accessible by fermentation. For this class of amino acids, commercialized biotranformations are either based on asymmetric synthesis starting from a prochiral compound or on (dynamic) kinetic resolutions of a racemate. As an illustration the published processes for (R)- and (S)-tert-leucine are outlined in Scheme 4.4. Both stereoisomers of tert-leucine have been used for fhe synfhesis of peptides that serve as protease inhibitors acting against viral infections (e.g. Hepatitis C, HIV), bacterial infections, autoimmune diseases and cancer [27]. This particular amino acid is versatile in fhese applications since fhe tert-butyl moiety provides resistance against endogenous proteases and can enhance the binding affinity of fhe peptide to fhe target protease. 

Benzoic acid, potassium salt EINECS 209-481-3 Potassium benzoate. Anti-corrosive, preservative, fermentation-inhibitor, antifungal agent for tobacco production, pyrotechnical additive. White solid soluble in H2O, EtOH. Am. Biorganics Lancaster Synthesis Co. Uallinckrodt Inc. Pentagon Chems. Lid VerdugtBV. 

For many plants, methyl jasmonate is a key elicitor, which initiates a series of response mechanisms to herbivores, like the synthesis of protease inhibitors and the increased formation of secondary metabolites (cf section 3.3- Jasmonoids). The effects were already well-known for tomato and tobacco plants, but also for Catharanthus and Cinchona seedlings and for soya beans. In the case of yew cells, this additive enabled to increase the paclitaxel production from 3 to 117 mg, and later to 295 mg per litre of fermentation broth. 

In 2009, Nakamura and co-workers [8] developed an organocatalytic aldol reaction between acetaldehyde 4 and dibromoisatin 1 catalyzed by iV-heteroaryl-sulfonylprolinamide 5, to achieve (/ )-convolutamydine E (6) in high enantioselectivity, which was easily converted to (/ )-convolutamydine B (7) (Scheme 17.2). In the same year, the Hayashi group used the prolinol catalyst 10 for the synthesis of enantiomer of natural convolutamydine E ent-6) (Scheme 17.3) [9], and intermediate 12 could be easily transformed into CPC-1 (13), a new pyrrolidinoindoline alkaloid isolated by Takayama and co-workers [10]. In addition, 12 was easily converted to indoline fragment 14, a key intermediate for the syntheses of madindo-line A (15) and B (16), which are selective inhibitors of interleukin-6, isolated from the fermentation broth of Streptomyces nitrosporeus K93-0711 by Omura and coworkers [11]. 

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