Metallohelices: potential mimetics of α-helical peptides in cancer treatment?

Many traditional anticancer agents act by damaging cellular DNA, but the lack of selectivity offered by this approach commonly leads to undesirable side effects [1]. In addition, the genetic instability of cancer cells facilitates the development of resistance to particular drug pathways [2]. There is thus a drive to discover systems that exhibit different – perhaps more subtle – modes of action. Host defense peptides, which are expected to act by prohibiting cellular processes through reversible and selective biomolecular interactions, have been investigated as potential anticancer agents to this aim [3]. However, these innate proteins are not ideal drug candidates as, although their pharmacodynamic profiles are promising, they tend to suffer from poor pharmacokinetics [4]. The design of nonpeptide systems that are able to imitate some of the functions and structures of α-helices, but with more desirable drug-like properties is an area of intense investigation [5]. Such peptidomimetics could nevertheless be as costly and difficult to synthesize as peptides [6], and they commonly have low solubility in aqueous media [7]. In addition, the exquisite 3D architecture of the α-helix is difficult to achieve realistically using the rather flat topographies of conventional synthetic organic chemistry.