Bifunctional molecules with antibody-recruiting and entry inhibitory activity against the human immunodeficiency virus
The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-HI's, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by recruiting anti-DNP antibodies to gp120-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-HI's bind to gp120 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gp120-expressing cells. Compounds and methods are described herein.
1. A method of synthesizing a compound according to the chemical structure 16:
where n and n′ are each independently an integer from 1 to 6, or a pharmaceutically acceptable salt thereof,
comprising reacting compound 10
with compound 4
in the presence of tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 in dimethylformamide/water to produce compound 11 according to the chemical structure:
which is then reacted with N-(9-Fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSU) to produce compound 12
where Fmoc is a fluorenylmethoxycarbonyloxy group and Boc is a tertiarybuyloxycarbonyl group;
Compound 12 is then deprotected with trifluoroacetic acid to remove the Boc group to produce compound 13
or its triflouoroacetate salt, which is reacted with compound 2
to produce compound 14
which is deprotected to remove the Fmoc group to produce compound 15
compound 15 is then reacted with alkyne compound 8
where DNP is a dinitrophenyl group, in the presence of copper sulfate (CuSO 4 ) and ascorbate to produce compound 16 or a pharmaceutically acceptable salt thereof.
2. A compound according to the chemical structure:
where n and n′ are each independently an integer from 1-6, or a pharmaceutically acceptable salt thereof.
3. A compound of claim 2 according to the chemical structure:
where n is an integer from 1 to 6, or
a pharmaceutically acceptable salt thereof.
4. A compound of claim 2 according to the chemical structure:
where n and n′ are each independently an integer from 1-6, or a pharmaceutically acceptable salt thereof.