Bioactivity of metallodrugs

Abstract

Background: Decades after its discovery, the Human Immunodeficiency Virus-1 (HIV-1) remains a major threat to public health. Highly Active Antiretroviral Therapy (HAART) has been successful in the treatment of the virus; however these drugs are associated with a number of adverse effects often resulting in non-compliance by the patients and increasing an individual’s susceptibility to opportunistic infections such as tuberculosis and cervical cancer. It is therefore crucial to continue the development of treatments that are less toxic but still provide significant control of viral infection allowing the immune system crucial recovery time. Methods: Metals are known to possess medicinal properties and in this study the bioactivity of 12 gold, platinum and palladium based complexes was investigated for the ability to inhibit viral replication and/or selected opportunistic infections. The complexes (containing the metals) were compared to the associated ligands (non-metal containing precursors). Ligands and complexes are collectively called compounds. Direct inhibition of crucial HIV-1 enzymes was assessed and the effects of the compounds on cell proliferation were determined using flow cytometry and real-time cell analysis. The anti-tumour activity of the complexes was then measured on HeLa cells (a cervical cancer cell line) with compound specificity for tumour cell growth inhibition determined using Vero cells (a monkey kidney cell line). The complexes were further tested for their activity against Mycobacterium tuberculosis and the minimum inhibitory concentrations (MICs) for each compound determined. Results: Three of the 12 complexes exhibited activity against HIV-1 protease, with the gold based complex AE190 resulting in 71% enzyme inhibition at 10μM (p= 0.002). None of the compounds inhibited HIV-1 reverse transcriptase and 9 complexes had good chemotherapeutic activity, but low selectivity indices (SI values below 10). Only the bimetallic complex AE177 was active against HIV-1 integrase. The palladium based complexes AE188, AE189 and AE190 had good activity against M. tuberculosis with MIC values of 1.56 μM for all three complexes and an SI value of 5.19 for AE189. Conclusion: The metallic complexes presented in this report demonstrate potential for development into improved anti-retroviral therapies and in addition selected complexes demonstrated dual activity (not seen in HAART); where a single complex was active against two different targets in the HIV-1 life cycle (AE177) or against two separate infections (AE190 active against HIV and M. tuberculosis). The low selectivity of a drug does not necessarily prevent its clinical use (e.g. cisplatin) but in this case, low selectivity will be used to recommend modified synthesis for improved activity. The ligands were universally inactive demonstrating the importance of the metal in the observed biological activity.