Novel compounds inhibiting HIV infection, breast cancer metastasis, and bacterial growth
Shepard, Joyce Brewer
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We synthesized novel guanide, biguanide, phenylguanide, and naphthyguanide derived compounds on linear, branched, and dendrimer backbones that are effective inhibitors of HIV infection, breast cancer metastasis, and bacterial growth. HIV utilizes CXCR4 as a co-receptor for cellular entry. Blocking CXCR4 inhibits infection with X4 strains of the virus. Initial competition assays demonstrated that some of the phenylguanide compounds bound to CXCR4 with high affinity. The derivatives with high CXCR4 affinity inhibited X4 viral infection, but did not inhibit R5 or X4R5 viruses. Importantly, many cancers overexpress CXCR4, including breast cancer. CXCR4 activation leads to cellular chemotaxis, angiogenesis, and cell survival, all of which promote cancer survival and proliferation. Compounds with high CXCR4 affinity were evaluated for inhibition of breast cancer metastasis. In vitro toxicity of all the derivatives was determined, followed by in vitro migration inhibition. Three derivatives with the best selectivity indexes for CXCR4 were examined in an in vivo lung colony metastasis assay. Spermidine trisphenylguanide (SI = 1785) was evaluated at 50 micrometers, 200 micrometers, and 300 micrometers and showed increasing inhibition of lung metastases (P = 0.34, 0.3, 0.02, respectively). Spermidine bis-2-naphthylguanide (SI = 1230) and spermine tris-2-naphthylguanide (SI = 191) were evaluated at 100 micrometers and showed significant reduction of lung metastases (P = 0.1 and 0.04, respectively). The topical antiseptic biguanide chlorhexidine, is structurally similar to our derivatives. So, the derivatives were tested for antimicrobial activity against drug susceptible and resistant pathogenic Enterococcus, Staphylococcus, Acinetobacter, and Pseudomonas strains. THAM trisphenylguanide, DNT2300 biguanide and phenylguanide, and DNT2200 phenylguanide demonstrated broad spectrum bacteriocidal activity similar to chlorhexidine. Preliminary in vivo studies on mice treated with THAM trisphenylguanide either immediately after methicillin resistant Staphylococcus aureus (MRSA) infection or an hour post MRSA infection showed significant reductions in bacterial burden in the intraperitoneal cavity, heart and kidney in the immediate treatment group and slight reductions of bacterial burden in the one hour treatment group. This data shows the potential for treatment of MRSA infections with the tested compounds. Thus, different subsets of the novel guanide compounds discussed here can inhibit HIV infection, breast cancer metastasis, and bacterial growth.