Lyase inhibitors

Fig. 9.5 Structural formula of the 17a-hydroxylase-17,20-lyase inhibitor MH61.

A second enzyme system targeted for androgen inhibition is 17a-hydroxylase/17,20-lyase, which is the key enzyme that converts pregnenolone to DHAand, subsequently, to testosterone (Fig. 45.3). Because testosterone has androgenic activity, inhibition of its biosynthesis would be useful in treating androgen-dependent diseases, such as prostate cancer (130). Inhibitors of 17o-hydroxylase/17,20-lyase inhibitors could prevent androgen biosynthesis from both testes and adrenals and may provide effective treatment of patients with prostate cancer. 

S, Tasaka A (2011) Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Biooig Med Chem 19 6383-6399... 

Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, Asahi S, Miki H, Tasaka A, Kusaka M (2012) Orteronel (TAK-700X a novel non-steroidal 17,20-lyase inhibitor effects on steroid synthesis in human and monkey adrenal cells and seram steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol 129 115 128... 

Botzki, A., Salmen, S., Bernhardt, G., Buschauer, A. and Dove, S. (2005) Structure-based design of bacterial hyaluronan lyase inhibitors. QSAR Comb. Sci., 24, 458-469. 

SPL expression was seen to be downregulated in colon carcinoma (Oskouian et ah, 2006), but upregulated in ovarian cancer (Hibbs et ah, 2004) and atopic dermatitis (Seo et ah, 2006). Most importantly, SPL knockout mice feature postnatal mortality due to multiple congenital abnormalities, in particular of the vasculature (Schmahl et ah, 2007). Whether these findings would limit the usefulness of SIP lyase inhibitors as immunomodulatory drugs remains to be explored. 

D-Fructosamine undergoes Buchi cyclocondensation reaction with nitriles, providing access to a variety of disubstituted imidazoles (Scheme 45), some of which have been proposed as potential sphingosine-1-phosphate lyase inhibitors for the treatment of such autoimmune disorders as rheumatoid arthritis or multiple sclerosis. 

Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW (2003) Effects of novel 17a-hydroxylase/C 17,20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 84 555-562 Matsunaga N, Kaku T, Itoh F, Tanaka T, Kara T, Miki H, Iwasaki M, Aono T, Yamaoka M, Ku-saka M, Tasaka A (2004) C17,20-lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors. Bioorg Med Chem 12 2251-2273... 

Yin L, Hu Q (2014) CYP17 inhibitors-abiraterone. Cl 7,20-lyase inhibitors and multi-taigeting agents. Nat Rev Urol 11 32 2... 

Feng X, Gao Z, Li S, Jones SH, Hecht SM (2004) DNA polymerase P lyase inhibitors from Maytenusputterlickoieks. JNat Prod 67 1744-1747... 

Phenylalanine ammonia-lyase (PAL EC 4.3.1.5) is a pivotal enzyme in controlling flow of carbon from aromatic amino acids to secondary aromatic compounds (Figure 1) (28). PAL primarily deaminates phenylalanine to form t-cinnamic acid, however, in many species, it also less efficiently deaminates tyrosine to form -coumaric acid. Because PAL is restricted to plants and is an important enzyme in plant development, Jangaard (29) suggested that PAL inhibitors might make safe and effective herbicides, however, in his screen of several herbicides, he found no compound to have a specific effect on PAL. This was also the case in studies by Hoagland and Duke (30, 31.) in which 16 herbicides were screened. 

Lauble, H., Miehlich, B., Forster, S. et al. (2002) Crystal structure of hydroxynitrile lyase from Sorghum bicolor in complex with the inhibitor benzoic acid a novel cyanogenic enzyme. Biochemistry, 41, 12043-12050. 

Inhibition of synthesis of the aromatic matrix by inhibitors of phenylalanine ammonia lyase causes the inhibition of deposition of aliphatic components and prevents development of diffusion resistance. Inhibition of synthesis of peroxidase, the enzyme involved in the deposition of the polymeric phenolic matrix, caused by iron deficiency, prevents deposition of aliphatic components of suberin. 

This compound was designed as potential inhibitor of chondroitin AC lyase from Flavobacterium heparinum, useful for the structural analysis of the enzyme active site. 

Carbon-carbon bond lyases, used in the reverse, synthetic direction have also enjoyed significant application in the pharmaceutical industry. For example 7/-acetyl-D-neuraminic acid (NANA), an intermediate in the chemoenzymatic synthesis of the influenza virus sialidase inhibitor zanamavir, may be synthesized using NANA aldolase. 

Inhibitor of cystathionine-processing enzymes (cystathionine 78, 189 /3-lyase) and cystalysin... 

Inhibitor of cystathionine /3-lyase from both Salmonella 78... 

Rye, C. S. Withers, S. G., The synthesis of a novel thio-linked disaccharide of chondroitin as a potential inhibitor of polysaccharide lyases. Carbohydr. Res. 2004, 339, 699-703. 

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