Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-19
2003-12-09
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C514S315000, C514S422000, C514S423000, C544S372000, C546S245000, C546S208000, C548S471000, C548S540000, C548S537000, C548S533000
Reexamination Certificate
active
06660741
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of organic chemistry and anti-tumor compounds. More specifically, the present invention relates to the asymmetric synthesis of (S,R.R)-(−)-actinonin and derivatives and analogs thereof and their uses as anti-tumor agents.
2. Description of the Related Art
(S,S,R)-(−)-Actinonin (1), was first isolated by Green and Singh from the Malayan strain of Actinomycete, Streptomyces sp. Cutter 12 (N.C.I.B. 8845) (FIG.
1
). It has been shown that actinonin exhibits antibiotic and anti-tumor properties (1-7). Studies have demonstrated that actinonin exhibits cytotoxicity towards tumor cell lines in vitro (4). Furthermore, actinonin induces GI arrest and apoptosis in human leukemia and lymphoma cells. It also treats AKR leukemia in AKR mice with minimal toxicity.
Although actinonin is commercially available and usually extracted from Actinomycete and Streptomyces bacteria, specifically
Streptomyces roseopallidus
(9, 10), the yield of compound derived is miniscule. For example, out of a typical ten day culture that yields eleven liters of filtrate, only 146 mg of pure actinonin are isolated. Currently, actinonin is synthesized by either of two synthetic schema. In Ollis' 1975 synthetic method, the synthesis of actinonin is non-stereoselective and the diastereomers have to be separated; difficult process producing small yields (11). Davies' 1992 synthesis is stereoselective and represents the first asymmetric synthesis of (−)-actinonin. An Fe(II)-based chiral auxiliary is used to introduce chirality at the &agr;-position of a carboxylic acid (13,14). However, this process causes disposal problems and therefore commercialization of the synthetic (−)-actinonin is doubtful. It is therefore necessary to develop a method for multi-gram synthesis of actinonin for further testing in various cancer cell lines and for animal studies.
The prior art is deficient in the lack of effective means of asymmetically synthesizing (S,R,R)-(−)-actinonin, its derivatives and its analogs for use as anti-tumor agents. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides a chemical compound comprising an analog or a derivative of (S,S,R)-(−)-actinonin having the structure:
where R
1
is an optionally substituted or halogenated alkyl, aryl, heteroalkyl or heteroaryl amine, where R
1
further comprises a cyclic or bicyclic structure; R
2
is methyl, CH
2
CH
3
, (CH
2
)
2
CH
3
, C(CH
3
)
3
, phenyl, 3,4-dichlorophenyl, biphenyl, benzyl, 4-hydroxybenzyl, piperidine, N-Boc-4-piperidine, CH
2
-(N-Boc-4-piperidine), 4-tetrahydropyran, CH
2
-4-tetrahydropyran, 3-methyl indolyl, 2-naphthyl, 3-pyridyl, 4-pyridyl, 3-thienyl; R
3
is R
2
or C
3-8
alkyl, R
4
is C
1-3
alkyl; and R
5
is NH
2
, OH, NHOH, NHOCH
3
, N(CH
3
)OH, N(CH
3
)OCH
3
, NHCH
2
CH
3
, NH(CH
2
CH
3
), NHCH
2
(2,4-(OCH3)
2
Ph, NHCH
2
(4-NO
2
)Ph, NHN(CH
3
)
2
, proline, or 2-hydroxymethyl pyrrolidine.
Another embodiment of the present invention provides a method for the treatment of a neoplastic disease comprising the step of administering to an individual in need of such treatment a pharmacologically effective dose of (S,S,R)-(−)-actinonin or other chemical compound disclosed herein or a pharmaceutically acceptable salt or hydrate thereof.
Yet another embodiment of the present invention provides a method of inhibiting the growth of a tumor cell comprising the step of contacting said cell with a pharmacologically effective dose of (S,S,R)-(−)-actinonin or other chemical compound disclosed herein or a pharmaceutically acceptable salt or hydrate thereof.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.
REFERENCES:
patent: 4929633 (1990-05-01), Shibahara et al.
patent: 5206384 (1993-04-01), Shibahara et al.
Borella Christopher
Bornmann William G.
Scheinberg David
Scher Howard
Sirotnak Francis
Adler Benjamin Aaron
McKane Joseph K.
Shiao Robert
Sloan-Kettering Institute for Cancer Research
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