Enediyne derivatives

Details Enediyne derivatives Enediyne derivatives

2000-07-21

2002-05-21

Trinh, Ba K. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S416000, C514S443000, C514S465000, C514S532000, C514S543000, C514S546000, C514S548000, C514S552000, C514S719000, C514S729000, C514S730000, C548S490000, C548S491000, C549S049000, C549S058000, C549S462000, C560S187000, C560S188000, C568S659000, C568S660000

Reexamination Certificate

active

06391916

ABSTRACT:

TECHNICAL FIELD
This invention relates to certain cyclic enediyne compounds and their precursor compounds, both of which have DNA cleavage, protein degrading and/or modulating antimicrobial and cytotoxic (antitumor) properties. More particularly, the invention relates to C
3
-substituted cyclodeca-1,5-diyn-3-enes and (E)-C
3
-substituted-4-(aryl- or heteroarylmethylidene)cyclodeca-1,5diynes, processes for preparing such compounds including a novel allylic rearrangement for converting the latter compounds into the former compounds, pharmaceutical compositions containing such compounds and their use for cleaving DNA, degrading or modulating a protein, inhibiting tumor growth, inhibiting microbial growth and treating cancer.
BACKGROUND OF THE INVENTION
The (Z)-hexa-1,5-diyn-3-ene moiety embedded in a 10-membered ring is highly strained but is a biologically important structural unit found in the naturally occurring enediyne antitumor antibiotics. See Nicolaou and Dai,
Angew. Chem. Int. Ed. Engl.,
30:1387 (1991). It is generally believed that the enediyne core found in the naturally occurring enediyne antitumor antibiotics, such as Calicheamicin &ggr;
1
1
, is bio-reductively activated and forms a 1,4-benzenoid diradical through cycloaromatization. The resultant radical species are reported to cause DNA strand scission by abstraction of hydrogen atom(s) from the sugar-phosphate backbone. Interaction of the carbon-centered radical with peptides and proteins has been reported. Cortazzo and Schor demonstrated enediyne-induced apoptosis in an article published in
Cancer Res.
56:1199 (1996). Damage to histones by enediynes are also known in the literature [Zein et al.,
Chem. Biol.
2:451 (1995); Zein et al.,
Proc. Natl. Acad. Sci. U.S.A.
90:8009 (1993)]. Recently, Jones et al. demonstrated that peptide radicals are generated from the interaction with enediyne-derived diradical species in an article published in
Org. Lett.
2:811 (2000). Reactive enediynes capable of generating a 1,4-benzenoid diradical through cycloaromatization are therefore useful compounds for biomedical applications.
Synthesis of the 10-membered ring enediynes is a challenging undertaking in organic synthesis because of the high strain energy associated with the bent acetylene units. The parent cyclodeca-1,5-diyn-3-ene was first synthesized, albeit in low yield, via a Ramberg-Bäcklund reaction using KO-t-Bu at −78° C. Nevertheless, this synthetic enediyne was confirmed to exert the natural product-like biological activities in causing both DNA strand breakage and cell death [Nicolaou et al.,
J. Am. Chem. Soc.,
110:4866 (1988); Nicolaou et al.,
J. Am. Chem. Soc.,
114:7360 (1992)]. Jones and co-workers used an intramolecular carbenoid coupling reaction performed at −45° C. in the presence of LiHMDS to close the 10-membered ring with significantly improved efficiency [Huber and Jones,
Tetrahedron Lett.,
35:2655 (1994); Jones et al.,
J. Chem.Soc., Chem. Commun.,
1791 (1995)]. Beau and Crévisy reported a synthesis of a 10-membered ring enediyne possessing a hydroxyl functionality by using the CrCl
2
—NiCl
2
-mediated ring closure as published in
Tetrahedron Lett.,
32:3171 (1991). However, the monocyclic enediynes are thermally unstable and readily undergo cycloaromatization at ambient temperature or above. The half-life of cyclodeca-1,5-diyn-3-ene was reported to be 18 hours at 37° C. by Nicolaou et a. as published in
J. Am. Chem. Soc.,
110:4866 (1988). The thermal instability of the simple unsubstituted monocyclic enediynes therefore renders their practical application difficult.
Various 10-membered ring enediynes have been synthesised which are substituted at one or more of the four —CH
2
positions between the two triple bonds, that is, the 7-, 8-, 9- and 10-positions. For instance, Suffert and Toussaint (
Tetrahedron Lett.,
38(31), 5507-5510, (1997)) disclose 10-membered ring enediynes which are substituted at the 7- and 8-positions and fused with a phenyl ring at the 9- and 10-positions and Dai et al (
J. Org. Chem.,
64,682-683, (1999)) discloses, inter-alia, (E)-3-hydroxy-4-benzylidene-10-anthraquinone-2-carbonyloxycyclodeca-1,5-diyne, 3-(1-hydroxy-1-phenyl)methyl-and 3-(1ethoxy-1-phenyl)methyl-7-anthraquinone-2-carbonyloxycyclodeca-1,5-diyn-3-ene.
SUMMARY OF THE INVENTION
It has now been discovered that certain novel C
3
-substituted cyclodeca-1,5-diyn-3-enes have improved thermal stability compared to the parent unsubstituted compound. Moreover, these compounds can be prepared from certain novel (E)-C
3
-substituted-4-(aryl- or heteroarylmethylidene)cyclodeca-1,5-diynes, which also have good thermal stability and act as enediyne prodrugs, by a novel method. Both the C
3
-substituted cyclodeca-1,5-diyn-3-enes and their precursors can be used as tools for interactions with DNA and proteins and as antimicrobial and antitumor agents.
According to a first aspect of the present invention there is therefore provided a compound having a nucleus of the general formula
which may be substituted or, more preferably, unsubstituted, wherein
X represents a hydroxyl group or an optionally substituted alkoxy or acyloxy group; and
Y represents an optionally substituted aryl or heteroaryl group; or,
in the case of formula B, X and Y together with the interjacent carbon atom represent an optionally substituted heterocyclic group;
or a salt thereof. If a compound of formula (A) or (B) is substituted, it is preferred that the substituent or substituents is or are located at one or more of the 7-, 8-, 9- and 10-positions of the ring.
In a second aspect, a process for preparing compounds of the general formula A is provided which comprises either cyclizing an appropriate 10-halo-2-(aryl- or heteroarylmethylidene)deca-3,9-diyn-1-al in the presence of a first-row transition metal (II) halide, prefereably chromium (II) and/or nickel (II) chloride, or cyclizing a 2-halo- or 2-trifluoromethanesulfonate-1-(aryl- or heteroaryl)-3-(hydroxy- or alkoxy)undeca-1-en-4,10-diyne in the presence of a palladium (0) catalyst and a suitable co-catalyst, preferably copper (I) or silver (I) iodide, to form compounds of formula A in which X represents a hydroxyl group or an optionally substituted alkoxy group. If desired, compounds of formula A in which X represents a hydroxyl group can then be reacted with a suitable carboxylic acid, acid anhydride and/or acid chloride in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to form compounds of formula A in which X represents an optionally substituted acyloxy group.
In a third aspect, a process for preparing compounds of the general formula B is provided which comprises reacting a compound of the general formula A in which X represents an optionally substituted acyloxy group in the presence of a lanthanide catalyst to form compounds of the general formula B in which X represents an optionally substituted acyloxy group or X and Y together with the interjacent carbon atom represent an optionally substituted heterocyclic group.
In a fourth aspect, a process for preparing compounds of the general formula B is provided which comprises reacting a compound of the general formula A in which X represents a hydroxyl group with a protic acid in the presence of a suitable alcohol or with a protic acid optionally in the presence of water to form compounds of the general formula A in which X represents a hydroxyl group or an optionally substituted alkoxy group.
In another aspect, pharmaceutical compositions are provided which comprise a carrier and, as active ingredient, a compound of the general formula A or B or a salt thereof.
Methods for inhibiting tumor growth, treating cancer, inhibiting microbial growth, cleaving DNA and degrading or modulating a protein are also provided which utilize a compound of the general formula A or B or a salt thereof.


REFERENCES:
Nicolaou and Dai,Angew, Chem. Int. Ed. Endl., 30:1387 (1991).
Cortazzo and Schor,Cancer Res.56:1199 (1996).
Zein et al.,Chem. Biol.2:451 (1995).
Zein et al.,Pr

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