Enzymes, inhibition/activation

Comparison of SQ 20,881 with fifty-seven related synthetic peptides indicated that the last five amino acids of the sequence are required for significant enzyme inhibiting activity (100). This nonapeptide, intravenously, lowered blood pressure even in patients with normal renin levels (101. 102). This effect is strongly augmented by sodium depletion. 

Microbial natural product chemistiy has generated a number of bioactive natural products. For instance cyclosporine A FK506 and rapamycin are used as immunosuppressants [16]. Other examples of microbial metabolites, having potential biomedical application include antihyperlipidemics, lovastatin and guggulsterone [17, 18]. The crude extracts of Mucor plumbeus exhibited acetylcholinesterase (AChE) enzyme inhibition activity. Our detailed chromatographic work on this crude extract resulted in the isolation of mucoralactone A (11), a novel steroid containing a lactone moeity incorporated in its structure. 

Compounds 13-18 were tested for acetylcholinesterase inhibition activity and it was found that compounds 13 and 14 exhibited acetylchohnesterase inhibition activity with IC values (inhibition of enzyme activity by 50%) of 17 and 13 pM, respectively. Compounds 15-18 showed moderate enzyme inhibition activity with ICj, values of 35, 80, 76, and 100 pM, respectively. This bioactivity data suggested that the higher enzyme inhibition potency of compounds 13 and 14 may hypothesized due to the presence of a tetrahydrofuran ring incorporated in their stractures. Fnrthermore, compounds 1 and 2 exhibited nearly the same bioactivity and this indicated that C-7 hydroxyl group does not play any role in enzyme inhibition activity. 

K. Tatsuta, Y. Niwata, K. Umezawa, K. Toshima, and M. Nakata, Syntheses and enzyme inhibiting activities of cyclophellitol analogs, J. Antihiot., 44 (1991) 912—914. 

Enzyme Inhibition/Activation. A major site of toxic action for metals is interaction with enzymes, resulting in either enzyme inhibition or activation. Two mechanisms are of particular importance inhibition may occur as a result of interaction between the metal and sulfhydryl (SH) groups on the enzyme, or the metal may displace an essential metal cofactor of the enzyme. For example, lead may displace zinc in the zinc-dependent enzyme 5-aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme-containing enzymes, such as cytochromes. 

Aoyama et al. have reported the synthesis of a number of l,3-diazetidine-2,4-dione analogues with a view to studying their enzyme inhibition activities (Scheme 46) <2001BML1691>. 

Peptides with angiotensin I-converting enzyme inhibition activity... 

Substituted-l-naphthols are synthetic phenolic compounds with dual inhibitory activities. The most active compound, 2-allyl-l-naphthol, is a very potent 5-LOX inhibitor with an IC50 value in nanomolar range and also has moderate COX enzyme inhibition activity. The compound also possesses excellent topical anti-inflammatory potency in the mouse ear edema model... 

Hara, Y., Matsuzaki, T., and Suzuki, T. 1987. Angiotensin I converting enzyme inhibiting activity of tea components. Nippon Nogeikagaku Kaishi 61 803-7. 

The same descriptor correlated well also with the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme inhibition activity of organophosphorus compounds. The best one-parameter correlation for the toxicity of organophosphorus compounds was achieved by using the normalized electronic moment (Me) [46]. 

CS 6-O-sulfate Esterification using inorganic acids Polyampholite soluble in water Anticoagulant Haemagglutination inhibition activities Anti sclerotic Antiviral Antihuman immunodeficiency virus Antibacterial Antioxidant Enzyme inhibition activities... 

Schmeda-Hirschmann, G., J.I. Loyola, S.R. Retamal, and J. Rodriguez. 1992. Hypotensive effect and enzyme inhibition activity of Mapuche medicinal plant extracts. Phytother. Res. 6 184-188. 

The activities were found to correlate with x (the first order valence molecular connectivity index) of P2/P2 substituents attached to the two nitrogens (N1 8c N3) and some indicator parameters. It was suggested [86] that the less polar and more hydrophobic substituent would be beneficial for improving the activities. The authors also found that the translation of the enzyme inhibition activity to antiviral potency is more sensitive for compoimds having dissimilar P2 and P2 substituents. 

One of the successful examples of employment of QSAR in the design and development of an HIV drug is the discovery of Indinavir (L-735,524) (2), one of the first HIVPI approved by the US-FDA. Holloway et aL [163] first reported this compound when they conducted SAR studies on a combined series of isostere derivatives of (43,44). A high correlation between the inter-molecular interaction energy ( int) calculated for HIVPR inhibitor complexes and enzyme inhibition activity was observed. QSAR 51-53 were developed for native, acetylpepstatin-inhibited and L-689,502-inhibited HIVPR, respectively [ 163]. X-ray coordinates and the force field technique were employed in the calculation of int (intermolecular interaction energy). In these QSAR, rev is the cross-validated correlation coefficient. 

Figure 8.13 Moving the 3-MeO on the pyri- reduced the enzyme inhibition activity signifi-dine ring in the pantoprazole to the 5-position cantly due to the undesired positioning of the improved the solution stability as expected 5-MeO. due to the reduced p/Q, which, however, also...

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