Lactacystin analogs

A compound having the following formula ##STR29## wherein Z.sup.1 is O, S, SO.sub.2, NH, or NR.sub.a, R.sub.a being C.sub.1-6 alkyl;

• X.sup.1 is O, S, CH.sub.2, two singly bonded H, CH(R.sub.b) in the E or Z configuration, or C(R.sub.b)(R.sub.c) in the E or Z configuration, each of R.sub.b and R.sub.c, independently, being C.sub.1-6 alkyl, C.sub.6-12 aryl, C.sub.3-8 cycloalkyl, C.sub.3-8 heteroaryl, C.sub.3-8 heterocyclic radical, or halogen, provided that when Z.sup.1 is SO.sub.2, X.sup.1 is two singly bonded H;
• Z.sup.2 is CHR.sup.1 in the (R) or (S) configuration, wherein R.sup.1 is H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, hydroxyl, halogen, a side chain of a naturally occurring amino acid, OR.sub.d, SR.sub.d, or NR.sub.d R.sub.e (each of R.sub.d and R.sub.e, independently, being H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or C.sub.2-5 alkynyl);
• Z.sup.3 is O, S, NH, or NR.sub.j, R.sub.j being C.sub.1-6 alkyl;
• X.sup.2 is O or S;
• and
• A.sup.1 is the side chain of any naturally occurring .alpha.-amino acid, or is of the following formula,
• --(CH.sub.2).sub.m --Y--(CH.sub.2).sub.n --R.sup.3 X.sup.3
• wherein Y is O, S, C.dbd.O, C.dbd.S, --(CH.dbd.CH)--, vinylidene, --C.dbd.NOR.sub.h, --C.dbd.NNR.sub.i R.sub.i', sulfonyl, methylene, CHX.sup.4 in the (R) or (S) configuration, or deleted, X.sup.4 being halogen, methyl, halomethyl, OR.sub.h, SR.sub.h, NR.sub.i R.sub.i', --NR.sub.i (OR.sub.h), or --NR.sub.i (NR.sub.i R.sub.i'), wherein R.sub.h is selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, and each of R.sub.i and R.sub.i', independently is selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyl;
• m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3;
• and R.sup.3 is straight chain or branched C.sub.1-8 alkylidene, straight chain or branched C.sub.1-8 alkylene, C.sub.3-10 cycloalkylidene, C.sub.3-10 cycloalkylene, phenylene, C.sub.6-14 arylalkylidene, C.sub.6-14 arylalkylene, or deleted, and X.sup.3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C.sub.1-6 alkyl)oxycarbonyl, (C.sub.7-14 arylalkyl)-oxycarbonyl, or C.sub.6-14 aryl;
• or R.sup.3 and X.sup.3 taken together are the side chain of any naturally occurring .alpha.-amino acid;
• where CHX.sup.4 is in the (S) configuration when X.sup.4 is hydroxyl and --(CH.sub.2).sub.n --R.sup.3 X.sup.3 is isopropyl, and the moiety --(CH.sub.2).sub.n --R.sup.3 X.sup.3 has between 5 and 20 carbon atoms when X.sup.4 is hydroxyl, m is 0, and Z.sup.1 is NH;
• provided that the compound does not have the following formula ##STR30##