US 5,965,718 A · Analogs of sarcodictyin and eleutherobin

Abstract

Sarcodictyin A and B, eleutherobin, and bioactive analogs thereof synthesized using solid phase and solution phase chemistries. The synthetic method employs an attachment of common precursors, e.g., compounds 1880 or 200, on a solid support for generating conjugates 230 and 240, followed by standard chemical manipulations. A combinatorial library of sarcodictyins and eletherobin analogs was constructed with modified C-8 ester, C-15 ester and C-4 ketal functionalities and was screened for activity with respect to tubulin polymerization and cytotoxic activity against tumor cells, including Taxol-resistant lines. Compounds 600, 610, 630, 660-700, 730, 760, 850, and 920 were identified to be of equal or superior biological activities as compared to their corresponding natural product.

A compound represented by the following structure:

##STR14## wherein:
R.sub.1 is a radical selected from the group consisting of --OH, OAc, and radicals represented by the following structures:
##STR15## R.sub.2 is a radical selected from the group consisting of --OH, --O(C.sub.1 -C.sub.6 alkyl), --OCH.sub.2 CF.sub.3, --O-iso-propyl, --O-tert-butyl, --O-benzyl, --OCH.sub.2 CH.dbd.CH.sub.2, --OCH.sub.2 CCH, --O(CH.sub.2).sub.2 --OH, --NHMe, --NMe.sub.2, --NHEt, --NEt.sub.2, --NH-n-propyl, --N-(propyl).sub.2, --NH-iso-propyl, --N-butyl.sub.2, --NH-benzyl, --N-benzyl.sub.2, --SH, --SMe, --SEt, --S-n-propyl, --S-iso-propyl, --S-n-butyl, --S-benzyl, and --S-phenyl;
R.sub.3 is a radical selected from the group consisting of --CH.sub.2 OC(O)CH.sub.3, --CH.sub.2 OC(O)-phenyl, --CH.sub.2 OC(O)O--CH.sub.3, --CH.sub.2 OC(O)NH-phenyl, --CH.sub.2 --OH, --CH(O), --CH.sub.2 --O-tri-isopropylsilyl, --CH.sub.2 O--Ac, --CH.sub.2 --F, --CH.sub.2 N.sub.3, --CH.sub.2 NAc, --CH.sub.2 NBz, --C(O)--CH.sub.2 CF.sub.3, --C(O)--CH.sub.2 CH.dbd.CH.sub.2, --C(O)--O--CH.sub.2 CH.sub.2 Cl, --C(O)O(CH.sub.2).sub.2 CH.sub.2 Cl, --C(O)O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2, --C(O)CH.sub.2 Ph, --C(O)CH.sub.2 -phenyl-OMe, --CH.sub.2 --O-tetrahydropyran, --CH.sub.2 --O--C(O)CHCl.sub.2, --CH.sub.2 --O--C(O)--CCl.sub.3, --CH.sub.2 --O--C(O)CHBr.sub.2, --CH.sub.2 --O--C(O)--CF.sub.3, --CH.sub.2 --O--C(O)CHPh.sub.2, EtC(O)--O--CH.sub.2 --, CH.sub.2 .dbd.CHC(O)--O--CH.sub.2 --, HC.tbd.CC(O)--O--CH.sub.2 --, n-propyl-C(O)--O--CH.sub.2 --, i-PrC(O)--O--CH.sub.2 --, cyclopropyl-C(O)--O--CH.sub.2 --, n-BuC(O)--O--CH.sub.2 --, i-BuC(O)--O--CH.sub.2 --, t-BuC(O)--O--CH.sub.2 --, cyclo-C.sub.6 H.sub.11 C(O)--O--CH.sub.2 --, phenyl-O--CH.sub.2 --, 2-furyl--C(O)--O--CH.sub.2 --, PhCH.dbd.CHC(O)--O--CH.sub.2 13, 2-thiophene-C(O)--O--CH.sub.2 --, (C.sub.1 -C.sub.6 alkyl)-O--CH.sub.2 --, i-propyl-O--CH.sub.2 --, allyl-O--CH.sub.2 --, benzyl-O--CH.sub.2 --, AcOCH.sub.2 CH.sub.2 --O--CH.sub.2 --, --COOH, --COO--(C.sub.1 -C.sub.6 alkyl), --COO-i-propyl, --COO-t-butyl, --COO-benzyl, --COOCH.sub.2 CH.dbd.CH.sub.2, --COO-CH.sub.2 C.tbd.CH, --COO-cyclo-C.sub.6 H.sub.11, --CONHBn, --CONH(C.sub.1 -C.sub.6 alkyl), --CONH-propyl, --COO--C.sub.8 H.sub.17, ##STR16## wherein R.sub.4 is a radical selected from the group consisting of --OH, --OAc, 2-Cl--AcO--, CCl.sub.3 C(O)O--, 2-Br--AcO--, CF.sub.3 C(O)O--, 2-phenyl-AcO--, (C.sub.1 -C.sub.6 alkyl)-C(O)O--, CH.sub.2 .dbd.CHC(O)O--, HC.tbd.--CC(O)O--, i-propyl-C(O)O--, cyclo-propyl-C(O)O--, i-butyl-C(O)O--, t-butyl-C(O)O--, cyclo-C.sub.6 H.sub.11 C(O)O--, phenyl-O--, 2-furyl--C(O)O--, PhCH.dbd.CHC(O)O--, and 2-thiophene-C(O)O--;
R.sub.5 is a radical selected from the group consisting of --OAc and --OH;
R.sub.6 is a radical selected from the group consisting of --OAc and --OH;
R.sup.7 is a radical selected from the group consisting of --H, and -methyl;
R.sub.8 is a radical selected from the group consisting of --OAc, 2-Cl--AcO--, CCl.sub.3 C(O)O--, 2-Br--AcO--, CF.sub.3 C(O)O--, 2-phenyl-AcO--, (C.sub.1 -C.sub.6 alkyl)-C(O)O--, CH.sub.2 .dbd.CHC(O)O--, HC.tbd.CC(O)O--, i-propyl-C(O)O--, cyclo-propyl-C(O)O--, i-butyl-C(O)O--, t-butyl-C(O)O--, cyclo-C.sub.6 H.sub.11 C(O)O--, phenyl-O--, 2-furyl-C(O)O--, PhCH.dbd.CHC(O)O--, and 2-thiophene-C(O)O--,
and the following provisos pertain:
a. if R.sub.1 is ##STR17## and R.sub.2 is --OH, then R.sub.3 cannot be simultaneously --CO.sub.2 -methyl or --CO.sub.2 -ethyl;
b. if R.sub.1 is ##STR18## and R.sub.2 is --O-methyl, then R.sub.3 cannot be ##STR19## wherein R.sub.4 is --OAc, R.sub.5 is hydroxy, R.sub.6 is hydroxy, and R.sub.7 is hydrogen;
c. if R.sub.1 is ##STR20## and R.sub.2 is --OH, then R.sub.3 cannot be ##STR21## wherein R.sub.4 is --OAc, R.sub.5 is hydroxy, R.sub.6 is --OAc, and R.sub.7 is hydrogen;
and
d. if R.sub.1 is ##STR22## and R.sub.2 is --OH, then R.sub.3 cannot be ##STR23## wherein R.sub.4 and R.sub.5 are --OAc, R.sub.6 is --OH, and R.sub.7 is hydrogen.

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Analogs of sarcodictyin and eleutherobin

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Analogs of sarcodictyin and eleutherobin

Life of this patent

Abstract

Claims8