Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top1) cleavage complexes and other 3'-end DNA lesions. TDP1 is a perspective target for anticancer therapy based on Top1-poison-mediated DNA damage. Several novel usnic acid derivatives with an enamine moiety have been synthesized and tested as inhibitors of TDP1. The enamines of usnic acid showed IC values in the range of 0.16 to 2.0 μM. These compounds revealed moderate cytotoxicity against human tumor MCF-7 cells. These new compounds enhanced the cytotoxicity of the established Top1 poison camptothecin by an order of magnitude.
Penicillin acylase from Alcaligenes faecalis has a very high affinity for both natural (benzylpenicillin, K m -0.0042 mM) and colorimetric (6-nitro-3-phenylacetamidobenzoic acid, K m = 0.0045 mM) substrates as well as the product of their hydrolysis, phenylacetic acid (A\ = 0.016 mM). The enzyme is partially inhibited at high benzylpenicillin concentrations but the triple SES complex formed still retains 43% of the maximal catalytic activity; the affinity of benzylpenicillin for the second substrate molecule binding site is much lower (As' = 54 mM) than for the first one. Phenylmethylsulfonyl fluoride was shown to be a very effective irreversible inhibitor, completely inactivating the penicillin acylase from A. faecalis in a few minutes at micromolar concentrations; this compound was used for enzyme active site titration. The absolute values of the determined kinetic parameters for enzymatic hydrolysis of 6-nitro-3-phenylacetamidobenzoic acid (k cat = 95 s _1 and k cat IK m = 2.1 X10 7 M _1 s _1 ) and benzylpenicillin (A cat = 54 s _1 and k cat IK m -1.3 X10 -7 M 1 s 1 ) by penicillin acylase from A. faecalis were shown to be highest of all the enzymes of this family that have so far been studied.
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