Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-12
2001-07-17
Oswecki, Jane C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S217000, C548S305100, C548S306100, C548S420000, C548S427000, C548S449000, C548S491000, C549S458000
Reexamination Certificate
active
06262271
ABSTRACT:
FIELD OF INVENTION
The invention relates to antitumor antibiotics. More particularly, the invention relates to analogs of CC-1065 and the duocarmycins having DNA alkylation and antitumor antibiotic activities.
BACKGROUND
(+)-CC-1065 (1) and the duocarmycins 2 and 3, illustrated in
FIG. 1
, are natural products having antitumor antibiotic activity through the alkylation of DNA. (Hanka, L. J., et al.
J. Antibiot.
1978, 31, 1211; Yasuzawa, T., et al.,
Chem. Pharm. Bull.
1995, 43, 378; and Takahashi, I., et al.,
J. Antibiot.
1991, 44, 1045.) Prior studies have shown that the natural products can withstand and may benefit from significant structural modifications to the alkylation subunit and that the resulting agents retain their ability to participate in the characteristic sequence-selective DNA alkylation reaction. (Boger, D. L., et al.,
Chem. Rev.
1997, 97, 787.) These structural modifications, and the definition of their effects have served to advance the understanding of the origin of the catalysis of the DNA alkylation reaction by 1-3. (Harper, D. E.
J. Am. Chem. Soc.
1994, 116, 7573; and Warpehoski, M. A., et al.,
J. Am. Chem. Soc.
1995, 117, 2951.)
These structural modifications have also served to advance the understanding of the origin of the DNA sequence selectivity of 1-3. (Warpehoski, M. A. In
Advances in DNA Sequence Specific Agents;
Hurley, L. H., Ed.; JAI: Greenwich, Conn., 1992; Vol. 1, p 217; Hurley, L. H. and Draves, P. In
Molecular Aspects of Anticancer Drug
-
DNA Interactions;
Neidle, S. and Waring, M., Eds.; CRC: Ann Arbor, 1993; Vol. 1, p 89; and Aristoff, P. A. In
Advances in Medicinal Chemistry;
JAI: Greenwich, Conn., 1993; Vol. 2, p 67). Two models have been proposed to explain the mechanism of the DNA sequence selectivity of 1-3. One model proposed by Boger states that the DNA sequence selectivity of 1-3 is determined by the AT-rich noncovalent binding selectivity of these agents and their steric accessibility to the adenine N3 alkylation site. (Boger, D. L., et al.,
Angew. Chem., Int. Ed. Engl.
1996, 35, 1439; and Boger, D. L., et al.,
Biorg. Med. Chem.
1997, 5, 263.) This noncovalent binding model accommodates and explains the reverse and offset 5 or 3.5 base-pair AT-rich adenine N3 alkylation selectivities of the natural and unnatural enantiomers of 1 (Boger, D. L., et al.,.
J. Am. Chem. Soc.
1990, 112, 4623; and Boger, D. L., et al,
Bioorg. Med. Chem.
1994, 2, 115) and the natural and unnatural enantiomers of 2-3. (Boger, D. L., et al.,.
J. Am. Chem. Soc.
1993, 115, 9872; and Boger, D. L., et al.,.
J. Am. Chem. Soc.
1994, 116, 1635.) This noncovalent binding model also requires that simple derivatives of the alkylation subunits exhibit alkylation selectivities distinct from the natural products. It also offers an explanation for the identical alkylation selectivities of both enantiomers of such simple derivatives (5′-A
A
>5′-T
A
), and the more extended AT-rich selectivity of the advanced analogs of 1-3 corresponds nicely to the length of the agent and the size of the required binding region surrounding the alkylation site. This model is further supported by the demonstrated AT-rich noncovalent binding of these agents. (Boger, D. L., et al.,
Chem.
-
Biol. Interactions
1990, 73, 29; and Boger, D. L., et al.,
J. Org. Chem.
1992, 57, 1277.) The model is also supported by the correspondence between the observed preferential noncovalent binding and the observed DNA alkylation of these agents. (Boger, D. L, et al.,
Bioorg. Med. Chem.
1996, 4, 859.) Also the observation that the characteristic DNA alkylation selectivity of these agents does not require the presence of the C-4 carbonyl or even the activated cyclopropane provides further support for the model, (Boger, D. L.et al.,
J. Am. Chem. Soc.
1991, 113, 3980.; and Boger, D. L., et al.
Proc. Natl. Acad Sci. U.S.A.
1991, 88, 1431.) The accuracy of this model is further demonstration of the complete switch in the inherent enantiomeric DNA alkylation selectivity that accompanied the reversal of the orientation of the DNA binding subunits with reversed versus extended analogs of the duocarmycins. (Boger, D. L., et al.,.
J. Am. Chem. Soc.
1997, 119, 4977; Boger, D. L., et al.,
J. Am. Chem. Soc.
1997, 119, 4987; and Boger, D. L., et al.,
J. Am. Chem. Soc.
1995, 117, 1443.)
The above AT-rich noncovalent binding model contrasts with an alternative proposal in which a sequence-dependent backbone phosphate protonation of the C-4 carbonyl activates the agent for DNA alkylation and controls the sequence selectivity. (Hurley, L. H.
J. Am. Chem. Soc.
1995, 117, 2371.)
Structural studies of DNA-agent adducts,
17-19
the C-4 carbonyl of the natural products projects out of the minor groove lying on the outer face of the complexes potentially accessible to the phosphate backbone. (Lin, C. H., et al.,
J. Mol. Biol.
1995, 248, 162.; and Smith, J. A., et al.,
J. Mol. Biol.
1997, 272, 237.) However, the relative importance of the C-4 carbonyl positioning to the properties of these agents has not be determined.
What is needed is a series of analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 which exploit the AT-rich noncovalent binding model and which retain their DNA binding and alkylating activity and selectivity. What is needed is series of analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 which incorporate of iso-CI and iso-CBI (6 and 7). Iso-CI and iso-CBI (6 and 7) are analogs of the CI and CBI alkylation subunits 4 and 5 wherein the key C-4 carbonyl is isomerically relocated to the C-6 or C-8 positions, now ortho to the cyclopropane, as illustrated in FIG.
2
. If the AT-rich noncovalent binding model is correct, the relocated carbonyls of iso-CI and iso-CBI (6 and 7) would project into the minor groove inaccessible to the phosphate backbone if participating in an analogous adenine N3 alkylation reaction.
SUMMARY
A series of bioactive analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 are synthesized. Each of the analogs includes iso-CI or iso-CBI (6 and 7) as a DNA alkylation subunit. The novel DNA alkylation subunits are then conjugated to known DNA binding subunits to form bioactive analogs of (+)-CC-1065 (1) and the duocannycins 2 and 3. Preferred DNA binding subunits are disclosed herein and in U.S. patent application Ser. No. 09/051,264, incorporated herein by reference.
2-(tert-Butyloxycarbonyl)-1,2,9,9a-tetrahydrocyclo-propa[c]benzo[f]indol-8-one (31, N-BOC-iso-CBI) and 1-(tert-butyloxycarbonyl)-4-hydroxy-3-[[(methanesulfonyl)oxy]methyl]-2,3-dihydroindole (19, seco-N-BOC-iso-CI) serve as preconjugate forms to the DNA alkylating subunits, i.e., iso-CI or iso-CBI (6 and 7). The approach for synthesizing compounds 31 and 19 was based on a directed ortho metallation of an appropriately functionalized benzene (13) or naphthalene (24) precursor to regiospecifically install iodine at the C-2 position. Conversion of these respective intermediates to the dihydroindole skeleton utilized an established 5-exo-trig aryl radical cyclization onto an unactivated alkene with subsequent TEMPO trap or the more recent 5-exo-trig aryl radical cyclization onto a vinyl chloride for direct synthesis of the immediate precursors. Closure of the activated cyclopropane to complete the iso-CBI nucleus was accomplished by a selective ortho spirocyclization.
Resolution and synthesis of a full set of natural product analogs and subsequent evaluation of their DNA alkylation properties revealed that the iso-CBI analogs react at comparable rates and retain the identical and characteristic sequence selectivity of CC-1065 and the duocarmycins. This observation is inconsistent with the prior art proposal that a sequence-dependent C-4 carbonyl protonation by strategically located DNA backbone phosphates controls the DNA alkylation selectivity but is consistent with the proposal that it is determined by the AT-rich noncovalent binding selectivity of the agents and the steric accessibility of the N3 alk
Lewis Donald G.
Oswecki Jane C.
The Scripps Research Institute
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