A A

4.6 ± 0.6 A

A = Hydrogen bonding acceptor group (electron donor group)

FIGURE 12.4 Proposed structural elements for P-gp recognition.

1. Type I units, which contain two hydrogen bond acceptor (electron donor) groups with a separation of 2.5 ± 0.5 A.

2. Type II units, which contain either three electron donor groups with a separation of 4.6 ± 0.6 A between the outer units, or two electron donor groups with the same spatial separation (Fig. 12.4).32 33

All molecules containing at least one Type I or Type II unit are predicted to be P-gp substrates, and the number and strength of these hydrogen bonds is related to the affinity to the protein. Further rationale for this theory comes from the fact that the transmembrane sequences of P-gp involved in substrate interaction contain a high number of amino acids with hydrogen bond donor sites such as the OH groups of Ser, Thr and Tyr, the NH2 group of Gln, the indolic NH group of Trp, and the SH group of Cys.

Another computer-aided substructural search coupled to a QSAR study of 609 compounds showed several pharmacophores, the most important of which was the fragment C-C-X-C-C, where X = N, O, nitrogen being preferentially tertiary. The most significant physicochemical property was found to be lipophilicity as measured by the (log P) parameter, while hydrophilic fragments such as carbox-ylic acids, phenols, anilines, and quaternary ammonium compounds are deacti-vating.34 These findings correlate well with an independent study concluding that an effective P-gp modulator candidate should have a log P higher than 2.92, a molecular axis with at least 18 atoms, a high energy value for the Highest Occupied Molecular Orbital (HOMO), and at least one tertiary, basic nitrogen atom.35 The role of lipids in MDR cells and the changes induced in the properties of membrane lipids by MDR modulators has been reviewed,36 and, in this context, it has been proposed that MDR reversers should be designed to be lipophilic (log P ~ 4) monobasic drugs with a near neutral pKa (7-8) in order to maximize favourable drug-membrane interactions.37 In addition, electrostatic interactions between the modulator and the membrane phospholipids also play an important role.

1.2.2. Structural manipulation of anticancer drugs aimed at circumventing P-gp

An alternative to the use of P-gp inhibitors is to introduce structural modifications in its substrates in order to increase passive diffusion, since the efflux pump cannot maintain a gradient and its pumping efficiency is poor when passive diffusion is sufficiently fast. This can be achieved by eliminating groups that solvate in water, decreasing their hydrogen bonding capacity by promoting intramolecular hydrogen bonds, and introducing lipophilic substituents such as halogen atoms, although there are still few published examples of this approach.38

1.2.3. Indirect inhibitors of MDR

The P-gp expression and function is influenced by several enzymes that, as cyclooxygenase 2 (COX-2)39 or glucosylceramide synthase,40 can be indirect targets in MDR inhibition. Certain compounds, such as the anticancer drug ectei-nascidin-743, can prevent mdrl gene expression,41 which can also be achieved by RNA interference through small RNA (siRNA) constructs.42 However, inhibition of the biosynthesis of the transport proteins by use of antisense oligonucleotides related to MRP or P-gp mRNAs seems to be of low clinical relevance in spite of previous good in vitro results.43

Because of the ATPase activity of P-gp, intracellular ATP concentration is important for P-gp function, and inhibitors of the ATPase activity of P-gp, like vanadate ion, have been proposed as adjuvants in the chemotherapy of solid tumors.44

Finally, besides MDR inhibition, a number of alternative approaches can be used to kill cells expressing the MDR phenotype. One of these approaches is based on optimization of drug delivery by use of nanoparticles or liposomes45 combined with hyperthermia.46 Another obvious alternative to circumvent P-gp resistance is the design of new anticancer agents that are not substrates of this transporter, but this aim would require that neither of the other ABC transporters be involved in chemoresistance.

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