CROSS-LINKING OLIGONUCLEOTIDES FOR CHEMOTHERAPY

SHORT OLIGODEOXYNUCLEOTIDES INCORPORATING NUCLEOTIDES MODIFIED BY THE ADDITION OF REACTIVE CROSS-LINKING ARMS WILLBE SYNTHESIZED. THESE OLIGONUCLEOTIDES SHOULD HYBRIDIZE WITH TARGET SEQUENCES IN MRNA OR DNA AND, ONCE BOUND, SHOULDCOVALENTLY CROSS-LINK WITH THE COMPLEMENTARY SEQUENCE VIA THE INCORPORATED MODIFIED NUCLEOTIDE. IN PARTICULAR, DERIVATIVES OF 4-AMINOPYRAZOLO(3,4-D)PYRIMIDINE, WITH A HALOALKYL OR SIMILAR SUBSTITUENT IN THE 3-POSITION, WILL BE PREPARED. THESE DERIVATIVES ARE ISOSTERIC WITH A 7-SUBSTITUTED PURINE AND SHOULD BE CAPABLE OF CROSS-LINKING WITH THE 7-POSITION OF A PURINE IN AN ADJACENT BASE PAIR OF THE COMPLEMENTARY STRAND. THIS MODIFIED NUCLEOSIDE WILL BE CONVERTED INTO A BLOCKED PHOSPHORAMIDITE AND INCORPORATED INTO AN OLIGONUCLEOTIDE ON A DNA SYNTHESIZER. THIS OLIGONUCLEOTIDE WILL BE TESTED FOR COVALENT CROSS-LINKING TO COMPLEMENTARY AND NONCOMPLEMENTARYDNA RESTRICTION FRAGMENTS. SUCH ANTISENSE, CROSS-LINKABLE OLIGONUCLEOTIDES, DESIGNED TO MINIMIZE HOST TOXICITY, MAY BE USEFUL AS CHEMOTHERAPEUTIC AGENTS FOR INFECTIOUS DISEASESAND CANCER. THEY WILL BE TARGETED AT THE MRNA OR DNA OF MICROORGANISMS OR OF ANY CANCER TISSUE IN WHICH ARREARRANGEDONCOGENE IS EXPRESSED.