Enzyme inhibition by hydroxypyridinone iron chelators

Poster Session

Cyclic aquartemary

PI:

Sunday

15 September

8-substituted a-amino acids (1) are interesting

building blocks for the synthesis of peptidomimetics

as enzyme

There are a number of pathological processes which are associated

inhibitors. They are available by asymmetric Strecker synthesis, carried

with

out exemplarily with the chiral, prochiral (RS)-2-methylcyclohexanone,

dystrophy,

optically active a-methylbenzylamine

Either

effects of cysteine protease inhibitors has been found”. Among the

controlled oily mixtures of the four

most promising inhibitor classes are the epoxysuccinyl peptides. Little

kinetically or thermodynamically feasible

and trimethylsilylcyanide.

2-methyl-l(a-methylbenzylamino)cyclohexanecarbonitriies

were obtained initially. The hydrolysis of these a-aminonitrile mixtures gave the P-methyl-l (a-methylbenzylamino)cyclohexanecarboxamides as mixtures of four diastereomers in total yields up to 78%. which could

increased

activities

of

cysteine

proteases:

e.g.

muscular

arthritis, cancer or cataracts. Evidence for therapeutic

attention has been given to modification of the chemically reactive group of these inhibitors: the oxirane ring. Syntheses of peptides containing aziridine2,3dicarboxylic

acid as a

be separated into diastereomerically pure compounds by application of

reactive group which can also undergo nucleophilic attack by the

CC, Lobar-

thiolate of the enzyme’s active site is described. Their potency as

and preparative HPLC rsp.. Hydrogenolysis yielded the

four primary i-amino-2-methyl-cyclohexanecarboxamides,

which were

finally converted under acidic conditions into the aquartemary acid hydrochlorides.

a-amino

Based on two X-ray structures the absolute

irreversible

inhibitors of cysteine proteases has been evaluated.

Dependency of inhibition adivity on stereochemistry of the aziridine ring and the sequence of the peptide moiety has been analyzed.

configuration of all synthesized compounds could be deduced. The thermodynamically controlled reactions yielded the trans-configurated (1 R’,2R’)-1-amino-2-methylcyclohexanecarboxylic

acids as the major

products, whereas under kinetic control the cis-confrgurated (1 R’,2S’)l-amino-2-methyl-cyclohexanecarboxylic

acids dominated.

[“I Drugs of the future 1994, 19, 1040

A series of novet derivatives of phenylpropytsmine and propiophenone have been synthesized, and were found to possess considersble antiinftsrnmatory activity. For futher studies of the mechanism of their sntiin%untnstoryaction, 3&aminopropyl)-1-phenyipropytsrnine (A) and 2(2-hydroxy-1-ethyl)-ethylamino-propiophenone (B) were chosen as representatives of these new non-steroidal anti-inflammatories (NSAIDs). Thus, in this investigation, the inhibitory effect of these compounds on the inflammatory reactions caused by various phlogistic agents, is studied. Compounds A and B were found to exert potent inhibitory effect on the paw edema method, in comparison to indomethacin. The adjuvant induced arthritis (AID) is used as a model for the anti-inflammatory and/or immunosuppressive activity of compounds A and B. AID is considered to be one of the best experimental models for investigation of anti-inflammatory and immunosuppressive drugs and qufte close to the human rheumatoid arthrftii. The examined compounds suppressed the AID manifestations very effectively. Furthermore, these compounds were tested in vitro for their ability to inhibit the mitogenic response of lymphocytes, since it is well established that lymphocytes are involved in the pathogenesis of AID. Compound A dii not show any in vitro effect on sptenocytes, suggesting either that it possesses onty anti-inflammatory properties or may also have immunosuppressive properties by acting on specific cells. In contrast, suppression of the mitogenic response of splenocytes to Con-A by compound 8, suggests a direct actton on lymphocytes and

therefore possession of anti-infammatory and possible immunosuppressive properties. In conclusion, A and B are effective agents not only on acute but also on chronic and immune j-Wnmation.

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l.P.S.Do&in and R.C. Hider;Chemisby in Briikn,565-568,1990 2.S.Singh; Chemistryand Industry, 452-455,1994. 3.U.Uhlin and Ii.Ekluxl,Nature,370,533-536, 1994.