...on the rationalisation, design, optimisation and synthesis of novel phosphonium derived anti-cancer drugs

Establishing Anti-Cancer Phosphonium Salt Structure-activity Relationships by Phil

Contents:

• Part 1 - Cancer and the Mitochondria
• Part 2 - Electrophoretic Uptake and Selectivity
• Part 3 - QSAR Analysis of Phosphonium Salts
• Part 4 - Design and Optimisation of Phosphonium Salts
• Part 5 - Synthesis
• Appendix
• References

Abstract

Cancer affects nearly 300,000 people per year in the UK. There is a pressing need for new anti-cancer medications. Triphenylphosphonium (TPP) salts are emerging as potent, selective and non-toxic anti-cancer drugs, currently in pre-clinical trials. Their unique mode of selectivity is a result of attraction and accumulation to the mitochondria, caused by electrochemical abnormalities of cancer cells. Their mode of action is not well understood and the specific interactions that elicit anticancer effects are unknown.

Drug uptake into the mitochondria involves drug desolvation and factor that facilitate this enable direct membrane passage. The Nernt and Born equations can be used to predict drug-like behaviour. With these equations various physical and chemical features estimated can be correlated with activity so that predictions of accumulation and potency can be made. It is an objective to review the Nernst-Born model applied to TPP a range of anti-cancer phosphonium salts from the literature and correlating their properties to physiological activity and cancer selectivity.
Diverse TPP substituents do not appear to contribute significantly towards activity and are highly tailorable. There is a relationship between lipophilicity and potency, but this is complicated by variable factors of structural origin including H-bond donor and acceptor numbers, molecular mass range and counter-ion. Across series of related compounds there are strong trends for potency to increase with lipophilicity up to a maximum where potency plateaus. This suggests a potency-maximum for each series of compounds.

Various trends have been elucidated relating structure to activity of phosphonium salts. These trends and guidelines will help to directing selection of appropriate molecular features when designing TPPs. There are a few very promising TPPs in literature that look to, with some optimisation lend themselves to preclinical investigation.

Several new procedures to phosphonium salts have been proposed and several new design criteria. Some modular procedures and involving new ‘Click chemistry’ are reported, which have yet to be reported in literature and as a first of its kind they are particularly exciting. Finally, for the heavily optimised TP-197-D only time we tell whether these optimisations were known the authors, when they put forwards their own clinical trial candidates.

Next: Part 1