CYTOTOXIC-DRUG DELIVERING MOLECULES TARGETING HIV (CDM-HS), CYTOTOXIC ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS AND METHODS OF USE

摘要

The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as CDM-Hs, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by introducing cytotoxic moieties to gp120-expressing cells, thereby causing cell death and preventing cell infection and spread of HIV. It is shown that CDM-Hs bind to gp120 and gp-120 expressing cells competitively with CD4, and these compounds cause cell death of HIV-infected cells, thereby decreasing viral infectivity. Compounds and methods are described herein.

主权项

1. A CDM-Hs compound according to the general formula: Where CYT is a moiety of a cytotoxic agent capable of causing death of a cell into which it is introduced; VICB is a virus invasion cell binding moiety comprising a group which is capable of binding to gp120 envelope protein on HIV virus or a cell surface of CD4 cells which are infected with HIV (HIV+) in a patient or subject; LL is a labile linker molecule which chemically links CYT to a connector moiety CON in said compound, is optionally linked to [CON] through a second non-labile linker [NLL] and is labile when said compound enters a cell; NLL is a non-labile linker molecule which chemically links VICB to CON in a molecule; CON is a bond or a connector molecule which links LL or NLL to CYT and/or VICB; Each j is independently 0, 1, 2, 3, 4 or 5; Each k is independently 0, 1, 2, 3, 4 or 5, with the proviso that k and/or j is at least 1 when CON is a bond; Each m in a molecule is independently an integer from 1 to 25; Each n in a molecule is independently an integer from 1 to 15, or a pharmaceutically acceptable salt, stereoisiomer, solvate or polymorph thereof.