Analogs of duocarmycin and cc-1065

Details Analogs of duocarmycin and cc-1065 Analogs of duocarmycin and cc-1065

1999-11-09

2001-08-28

Solola, Taofiq A (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C548S421000, C548S429000

Reexamination Certificate

active

06281354

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The field of this invention is antitumor antibiotics. More particularly, the present invention relates to analogs of duocarmycin and CC-1065, which analogs have antitumor antibiotics activity.
BACKGROUND OF THE INVENTION
Duocarmycin SA (1) and duocarmycin A (2) constitute the parent members of a class of potent antitumor antibiotics related to CC-1065 (3) that derive their properties through a sequence selective alkylation of duplex DNA (FIG.
1
). Since their disclosure, substantial efforts have been devoted to defining the characteristics of their DNA alkylation reactions, to determining the origin of their DNA alkylation selectivity, and to defining fundamental relationships between structure, functional reactivity, and biological properties.
Three models have been advanced to account for the DNA alkylation sequence selectivity. One model proposes a sequence-dependent phosphate protonation of the C4 carbonyl which activates the agent for DNA alkylation. (Warpehoski, M. A.; Hurley, L. H.
Chem. Res. Toxicol
. 1988, 1, 315; Hurley, L. H.; Reynolds, V. L.; Swenson, D. H.; Petzold, G. L.; Scahill, T. A.
Science
1984, 226, 843. Reynolds, V. L.; Molineux, I. J.; Kaplan, D. J.; Swedson, D. H.; Hurley, L. H.
Biochemistry
1985, 24, 6228. Hurley, L. H.; Lee, C.-S.; McGovren, J. P.; Warpehoski, M. A.; Mitchell, M. A.; Kelly, R. C.; Aristoff, P. A.
Biochemistry
1988, 27, 3886. Scahill, T. A.; Jensen, R. M.; Swenson, D. H.; Hatzenbuhler, N. T.; Petzold, G.; Wierenga, W.; Brahme, N. D.
Biochemistry
1990, 29, 2852; Hurley, L. H.; Warpehoski, M. A.; Lee, C.-S.; McGovren, J. P.; Scahill, T. A.; Kelly, R. C.; Mitchell, M. A.; Wicnienski, N. A.; Gebhard, I.; Johnson, P. D.; Bradford, V. S.
J. Am. Chem. Soc
. 1990, 112, 4633; Lin, C. H.; Beale, J. M.; Hurley, L. H.
Biochemistry
1991, 30, 3597.) Another invokes alkylation at junctions of bent DNA without addressing the source of catalysis. (Lin, C. H.; Sun, D.; Hurley, L. H.
Chem. Res. Toxicol
. 1991, 4, 21. Lee, C.-S.; Sun, D.; Kizu, R.; Hurley, L. H.
Chem. Res. Toxicol
. 1991, 4, 203. Lin, C. H.; Hill, G. C.; Hurley, L. H.
Chem. Res. Toxicol
. 1992, 5, 167. Ding, Z.-M.; Harshey, R. M.; Hurley, L. H.
Nucl. Acids. Res
. 1993, 21, 4281. Sun, D.; Lin, C. H.; Hurley, L. H.
Biochemistry
1993, 32, 4487. Thompson, A. S.; Sun, D.; Hurley, L. H.
J. Am. Chem. Soc
. 1995, 117, 2371.) A third model is based on the premise that distinct alkylation selectivities are controlled by the AT-rich noncovalent binding selectivity of the agents and their steric accessibility to the adenine N3 alkylation site. (Boger, D. L.; Johnson, D. S.
Angew Chem., Int. Ed. Engl
. 1996, 35, 1439. Boger, D. L.; Johnson, D.
S. Proc. Natl. Acad. Sci., U.S.A
. 1995, 92, 3642. Boger, D. L.
Acc. Chem. Res
. 1995, 28, 20. Boger, D. L.
In Advances in Heterocyclic Natural Product Synthesis
; Pearson, W. H., Ed.; JAI: Greenwich, 1992; Vol. 2, 1. Boger, D. L.
Chemtracts: Org. Chem
. 1991, 4, 329. Boger, D. L. In
Proc. R. A. Welch Found. Conf. Chem. Res
., XXXV,
Chem. Frontiers Med
. 1991, 35, 137. Boger, D. L. In
Heterocycles in Bioorganic Chemistry
; Bergman, J.; van der Plas, H. C.; Simonyl, M., Eds.; Royal Soc. of Chem.: Cambridge, 1991; 103. Coleman, R. S.; Boger, D. L. In
Studies in Natural Product Chemistry
; Rahman, A.-u.-, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, 301; Boger, D. L.; Johnson, D. S.; Yun, W.; Tarby, C. M.
Bioorg. Med. Chem
. 1994, 2, 115. Boger, D. L.; Munk, S. A.; Zarrinmayeh, H.; Ishizaki, T.; Haught, J.; Bina, M.
Tetrahedron
1991, 47, 2661. Boger, D. L.; Coleman, R. S.; Invergo, B. J .; Sakya, S. M.; Ishizaki, T.; Munk, S. A.; Zarrinmayeh, H.; Kitos, P. A.; Thompson, S. C.
J. Am. Chem. Soc
. 1990, 112, 4623.) This latter proposal accommodates and explains the reverse and offset 5 or 3.5 base-pair AT-rich adenine N3 alkylation selectivities of natural and unnatural enantiomers of duocarmycin and CC-1065 and offers a beautiful explanation for the identical alkylation selectivities of both enantiomers or simple derivatives thereof. Further support for this model includes the demonstrated AT-rich noncovalent binding of the agents, their preferential noncovalent binding coincidental with DNA alkylation, the demonstration that the characteristic DNA alkylation is also observed with isomeric alkylation subunits (e.g., iso-CI and iso-CBI), and that it does not require the presence of the C4 carbonyl or even the activated cyclopropane.
In previous studies, the issue of catalysis with the noncovalent binding model has not been addressed. The chemical stability of duocarmycin and CC-1065 and the acid-catalysis requirement for addition of typical nucleophiles has led to the assumption that the DNA alkylation must also be an acid-catalyzed reaction. Although efforts have gone into supporting the extent and role of this acid catalysis, it remains largely undocumented for the DNA alkylation reaction. At pH 7.4, the DNA phosphate backbone is fully ionized (0.0001-0.00004% protonated). Consequently, it is unlikely that catalysis is derived from a phosphate backbone delivery of a proton to the C4 carbonyl as advanced in the alkylation site model. Consistent with this, the rate of the DNA alkylation reaction for duocarmycin SA exhibits only a very modest pH dependence below pH 7 and essentially no dependence in the more relevant pH 7-8 range.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides analog compounds of duocarmycin SA, duocarmycin A and CC-1065. An analog compound of the invention is represented by the following structure:
where said compound is fused to a first ring having a first vinylene group V
1
between R
1
and R
2
, said first ring being one of the following structures, A, B, or C:
where said compound is also fused to a second ring having a second vinylene group V
2
between R
3
and R
4
, said second ring being one of the following structures, D, E, or F:
wherein R
5
is a hydrogen, —CO
2
(C
1
-C
6
(alkyl)) or a radical represented by the following structure, G:
where R
6
is hydrogen or C
1
-C
6
(alkyl); R
7
is —H, —CO
2
(C
1
-C
6
(alkyl)), —CO(C
1
-C
6
(alkyl)), —CO
2
-tert-butyl, or —COR
14
; R
8
is hydrogen or a first N-substituted pyrrolidine ring being fused at a third vinylene group V
3
between R
8
and R
9
represented by the following structure, H:
where R
9
is: —NH—C(O)—; R
10
and R
11
, are each independently hydrogen, —O—C
1
-C
6
(alkyl) or —C
1
-C
6
(alkyl), wherein the —NH group is directly attached to G at the R
9
position and the C(O)— group is directly attached to the first ring at the R
5
position, if R
8
, R
10
and R
11
are each hydrogen; said first N-substituted pyrolidine ring radical, H, being fused at the third vinylene group V
3
between R
8
and R
9
; and a radical represented by the structure, I:
 wherein the —NH group is directly attached to G at the R
9
position and the C(O)— group is directly attached to the first ring at the R
5
position, if R
8
, R
10
and R
11
are each hydrogen; with the following provisos:
if R
8
participates in the first N-substituted pyrrolidine ring, then R
9
also participates in the first N-substituted pyrrolidine ring;
if R
9
participates in the first N-substituted pyrrolidine ring, then R
8
also participates in the first N-substituted pyrrolidine ring;
if R
8
and R
9
participate in the first N-substituted pyrrolidine ring, then R
10
and R
11
are hydrogen; R
12
is —C(O)— and a diradical represented by the following structure, J:
wherein the —C(O) group is directly attached to H at the R
12
position and the N—C(O)— group is directly attached to the first ring at the R
5
position; R
13
is hydrogen or C
1
-C
6
(alkyl); R
14
is hydrogen, C
1
-C
6
(alkyl), —O—(C
1
-C
6
(alkyl)), or a radical represented by the structure, K:
where R
15
is hydrogen or a second N-substituted pyrolidine ring being fused at a fourth vinylene group V
4
between R
15
and R
16
represented by the following structure, L:
where R
16
is:
—O—(C
1
-C
6
(alkyl)), C
1
-C
6
(alkyl), NH
2
or said second N-substituted pyr

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