Lipophilicity antitumor drugs

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Incorporation of Lipophilic Antitumor and Antiviral Drugs into the Lipid Bilayer of Small Unilamellar Liposomes... 

Figure 10.6 The antitumoral camptothecin (CPT), a lipophilic drug extracted from the Chinese tree Camptotheca acuminata, can be incorporated into the liposome bilayer due to its lipophilic character. The CPT-containing liposomes are studied as antitumor drug formulations. (Modified from Stano et al 2004.)...

Particularly facile is trifluoroacetylation of daunomycin, which can be achieved by action of ethyl trifluoroacetate in the presence of triethylamine or other basic catalyst. The product of this reaction has considerably reduced cytotoxicity, but it can be more easily accumulated in a cell because it is no longer a substrate for the Pgp efflux pump. Its lipophilic esters (products of acylation at C-14 primary hydroxyl group) became experimental antitumor drugs [120,121] and valrubicin (AT-trifluoroacetyl-H-O-valeroyldoxorubidn) was registered for use in bladder cancer treatment. A new method for preparation of the drug, which consists of efficient two-step chemoenzymatic transformation of Dox was disclosed recently [122]. 

Thus, the conclusions from equation (27) are that the two activities cannot be separated, but for optimum hypotensive activity the lipophilicity of the compounds should be around 1.5. Such analogs can readily cross the blood-brain barrier and their central effect will override the peripheral effect. All other attempts to find chemically related analogs with improved selectivity must fail. Thus, no more syntheses and testing of compounds within this series need to be performed. Several other examples are known where desired activities have been compared with toxicides, especially for antitumor drugs. In some cases the syntheses of further analogs were stopped because no better therapeutic indices could be expected. " ... 

Pignatello R, et al. Effect of liposomal delivery on in vitro antitumor activity of lipophilic conjugates of methotrexate with lipoamino acids. Drug Deliv 2003 10 95. 

A structure-related disadvantage of the duplex drugs is that upon enzymatic cleavage of the phosphodiester bonds, a 1-to-l ratio of nucleoside to nucleotide is obtained (see Figure 7.7-6). Thus, the desired 5 -phosphorylated nucleotide is only formed at maximally 50%. Additionally, one of the two nucleosides has to be transformed into a lipophilic derivative without loss of antitumor or antiviral activity. On the other hand, it was shown that the lipophilic derivatization of nucleosides can result in enhanced activity and modulation of cell specificity [106]. 

Finally, several QSAR studies (8,10,11) have shown that the acute toxicity and antitumor potency of substituted aniline mustards in vivo are also dominated by the electronic properties of substituent groups, although additional factors such as drug lipophilicity play a role in these systems. For example, the potencies (dose of drug required to provide an increase in lifespan or 25%) or a series of compounds against the B-16 melanoma in mice were best fitted by Equation 4 (equation 8 of ref. JJ). 

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