Non-naturally occuring dynemicin analogs are provided, which are useful as DNA cleaving agents, cytotoxic agents, and/or anti-tumor compounds. Methods of making dynemicin analogs are also provided.

FIELD OF THE INVENTION 
The invention relates to dynemicin analogs which are DNA-cleaving, 
cytotoxic and/or anti-tumor compounds, and to methods of making such 
dynemicin analogs. 
BACKGROUND OF THE INVENTION 
Dynemicin A, shown below in Structure 108, is a potent antibacterial and 
anticancer agent recently isolated from Micromonospora chersina (see U.S. 
Pat. No. 4,916,065): 
##STR1## 
Dynemicin A shares molecular structure similarities with the calicheamicin 
and esperamicin antibiotic classes, in that it contains an enediyne 
bridge. Due to its complex structure and sensitive functional groups, its 
synthesis has proven difficult if not impossible. 
For example, portions of the dynemicin molecule have been synthesized 
(Porco et al., J. Am. Chem. Soc. 1990, 112:7410-7411; Chikashita et al., 
J. Org. Chem. 1991, 56:1692-1694; Wood et al., J. Am. Chem. Soc. 1992, 
114:5898-5900). Di- and tri-O-methyl dynemicin A methyl esters have also 
reportedly been made (Taunton et al., J. Am. Chem. Soc. 1993, 
115:10378-10379). 
As a result of this difficulty, several groups have developed synthetic 
pathways for dynemicin intermediates. For example, U.S. Pat. Nos. 
5,276,159 and 5,281,710 describe a variety of dynemicin intermediates. It 
is far from clear, however, whether any dynemicin analogs containing an 
anthraquinone structure can be made from the protocols disclosed. 
U.S. Pat. No. 5,162,330 describes dynemicin C, obtained by cultivating a 
mutant strain of Micromonospora chersina. A triacetate derivative 
reportedly was prepared via acetylation. 
However, a flexible synthesis has not been developed. Accordingly, it is an 
object of the present invention to provide novel dynemicin analogs. Such 
analogs preferably have DNA cleaving, antibiotic and antitumor activities. 
A further object is to provide methods for the synthesis of such dynemicin 
analogs. 
SUMMARY OF THE INVENTION 
In accordance with the foregoing objects, the invention provides quinone 
imine dynemicin analogs having the formula: 
##STR2## 
wherein: R.sub.1 is hydrogen, C1-C16 straight chain or branched alkyl, 
protected alkyl alcohol, protected alkyl thiol; 
R.sub.2 is hydrogen, C1-C16 straight chain or branched alkyl, protected 
alkyl alcohol, or protected alkyl thiol; 
R.sub.7 is hydrogen, hydroxyl, alkyl ether, or trialkyl silyl ether; 
R.sub.8 is hydrogen, C1-C16 straight chain or branched alkyl, aryl, 
protected alkylamine, protected alkylthiol, or with R.sub.9 and the 
unsaturated vinylene between R.sub.8 and R.sub.9 form an aryl group; 
R.sub.9 is hydrogen, C1-C16 straight chain or branched alkyl, aryl, a 
tethering group, protected alkylamine, protected alkylthiol, or with 
R.sub.8 and the unsaturated vinylene between R.sub.8 and R.sub.9 an aryl 
group; 
R.sub.10 is hydrogen or a protecting group or absent if Y is a double bond; 
R.sub.18 is carbonyl oxygen, hydroxyl, or alkyl silyl ether; 
X is a double or a single bond; and 
Y is a double or a single bond; 
wherein when X is a single bond, 
R.sub.3 is hydrogen, carbonyl oxygen, hydroxy, alkyl ether, carboxyl, 
alkyl, or halogen; 
R.sub.4 is hydrogen, alkyl ether, hydroxy, alkyl, halogen, or is absent 
when R.sub.3 is carbonyl oxygen; 
R.sub.5 is hydrogen, carbonyl oxygen, oxygen, alkyl, hydroxy, halogen, 
alkyl ether; 
R.sub.6 is hydrogen, hydroxy, halogen, alkyl group, alkyl ether, alkyl or 
is absent when R.sub.5 is carbonyl oxygen; 
wherein when X is a double bond, 
R.sub.3 is is absent; 
R.sub.4 is hydrogen, halogen, carboxy, alkyl ester, alkyl ether or COZ, 
wherein Z is primary or secondary amine, alkylthiol or alkyl; 
R.sub.5 is is absent; and 
R.sub.6 is hydrogen, halogen, oxygen, carboxy, alkyl ester, alkyl ether or 
COZ, wherein Z is primary or secondary amine, alkylthiol or alkyl; 
wherein when Y is a single bond, 
the ring to which R.sub.18 is attached is aromatic; and 
R.sub.18 is hydroxyl or alkyl silyl ether; 
wherein when Y is a double bond, 
the ring to which R.sub.18 is attached has an additional double bond; and 
R.sub.18 is carbonyl oxygen. 
In another aspect, the present invention provides non-naturally occuring 
anthraquinone dynemicin analogs. These dynemicin analogs have the general 
formula: 
##STR3## 
wherein R.sub.1 is hydrogen, C1-C16 straight chain or branched alkyl, 
protected alkyl alcohol, protected alkyl thiol; 
R.sub.2 is hydrogen, C1-C16 straight chain or branched alkyl, protected 
alkyl alcohol, or protected alkyl thiol; 
R.sub.7 is hydrogen, hydroxyl, alkyl ether, oxygen, or trialkyl silyl 
ether; 
R.sub.8 is hydrogen, C1-C16 straight chain or branched alkyl, aryl, 
protected alkylamine, protected alkylthiol, or with R.sub.9 and the 
unsaturated vinylene between R.sub.8 and R.sub.9 form an aryl group; 
R.sub.9 is hydrogen, C1-C16 straight chain or branched alkyl, aryl, 
protected alkylamine, protected alkylthiol, or with R.sub.8 and the 
unsaturated vinylene between R.sub.8 and R.sub.9 an aryl group; 
R.sub.10 is hydrogen or a protecting group or is absent if Y is a double 
bond; 
R.sub.11 is carbonyl oxygen, hydroxy, hydrogen, alkyl ether, trialkyl silyl 
ether, alkyl silyl ether, or alkyl; 
R.sub.12 is hydrogen, alkyl ether, or alkyl; 
R.sub.13 is hydrogen, alkyl, or together with R.sub.14 and the unsaturated 
vinylene group between R.sub.13 and R.sub.14 form an aryl group; 
R.sub.14 is hydrogen, alkyl, or together with R.sub.13 and the unsaturated 
vinylene group between R.sub.13 and R.sub.14 form an aryl group; 
R.sub.15 is hydrogen, alkyl ether, or alkyl; 
R.sub.16 is carbonyl oxygen, hydroxy, hydrogen, alkyl ether, trialkyl silyl 
ether, alkyl silyl ether, or alkyl; 
R.sub.17 is hydroxy or carbonyl oxygen; 
X is a double or a single bond; and 
Y is a double or a single bond; 
wherein when X is a single bond, 
R.sub.3 is hydrogen, carbonyl oxygen, hydroxy, alkyl ether, carboxyl, 
alkyl, or halogen; 
R.sub.4 is hydrogen, alkyl ether, hydroxy, alkyl, halogen, or is absent 
when R.sub.3 is carbonyl oxygen; 
R.sub.5 is hydrogen, oxygen, carbonyl oxygen, hydroxy, halogen, alkyl 
ether, or alkyl; 
R.sub.6 is hydrogen, hydroxy, halogen, alkyl group, alkyl ether, alkyl or 
is absent when R.sub.5 is carbonyl oxygen; 
wherein when X is a double bond, 
R.sub.3 is is absent; 
R.sub.4 is hydrogen, halogen, carboxy, alkyl ester, alkyl ether or COZ, 
wherein Z is primary or secondary amine, alkylthiol or alkyl; 
R.sub.5 is is absent; and 
R.sub.6 is hydrogen, halogen, oxygen, carboxy, alkyl ester, alkyl ether or 
COZ, wherein Z is a primary or secondary amine, alkylthiol or alkyl. 
A further aspect provides methods of making dynemicin analogs comprising 
reacting dienes with quinone imines. 
An additional aspect provides methods of inhibiting the growth of cells, 
and pharmaceutical compositions comprising the dynemicin analogs of the 
present invention.