Pharmacological aspects of cytotoxic polyamine analogs and derivatives for cancer therapy

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Abstract

During the past 20 years, numerous derivatives and analogues of spermidine (Spd) and spermine (Spm) were synthesized with the aim to generate a new type of anticancer drug. The common denominator of most cytotoxic polyamine analogues is their lipophilicity, which is superior to that of the parent amines. The natural polyamines bind to polyanions and to proteins with anionic binding sites. Their hydrophilicity/hydrophobicity is balanced, allowing them to perform physiological functions by interacting with some of these anionic structures, without impairing the functionality of others. Because the attachment of lipophilic substituents to the polyamine backbone increases the binding energy, lipophilic polyamine derivatives affect secondary and tertiary structures of a larger number of macromolecules than do their natural counterparts. In addition, lipophilicity improves the blood–brain barrier transport and thus enhances CNS toxicity. Close structural analogues of spermidine and spermine mimic the natural polyamines in regulatory functions. The cytotoxic mechanisms of analogues with a less close structural resemblance to spermidine or spermine have not been completely clarified. The displacement of spermidine from functional binding sites and the consequent prevention of its physiological roles is a likely mechanism, but many others may play a role as well. Up to now, polyamine analogues were conceived without specific growth-related targets in mind. To develop therapeutically useful drugs, it will be imperative to identify specific targets and to design compounds that interact selectively with the target molecules. It will also be necessary to include, at an early state of the work, pharmacological and toxicological considerations, to avoid unproductive directions.

Introduction

Putrescine (Put), spermidine (Spd), and spermine (Spm), commonly designated as polyamines, are polycations with flexible aliphatic carbon chains. They are formed and stored by nearly all procaryotic and eucaryotic cells (Cohen, 1998). Fig. 1 illustrates the major metabolic reactions of polyamines in mammalian cells. There is evidence for a great diversity of functions in cell biology from growth-related effects (Cohen, 1998) to radical scavenging (Lovaas, 1997, Ha et al., 1998b) and immunomodulation (Seiler & Atanassov, 1994). Interactions with receptors suggest, among others, involvement in the regulation of ion movements (Williams, 1997).

Owing to their ability to affect or stabilize conformations of nucleic acids and of proteins with anionic binding sites, numerous metabolic and other cell functions, including gene expression, are modulated by changes in polyamine concentrations (Cohen, 1998, chapters 22 and 23; Childs et al., 2003). Disregarding their ability to form derivatives in analogy with other biogenic amines, polyamine functions depend mainly on the formation of ion bonds with the target molecules. The pK values of the amino groups are such that at, physiological ion concentrations and pH, protonation is nearly complete. Binding affinity increases with the number of protonated amino groups. The interactions of the polyamines with polyanions (single- and double-stranded DNA, RNAs, etc.) can be described as tight but delocalized binding, in which the cations are free to diffuse along the polyanion backbone (Manning & Ray, 1998). Some functions are presumed to depend on the number of protonated amino groups and the precise length of the flexible linear carbon chains between the protonated primary and secondary amino groups. This assumption is based, among others, on the specific binding of Spd and Spm to tRNAs (Quigley et al., 1978, Cohen, 1998, Igarashi & Kashiwagi, 2000), the growth function of Spd, and the fact that a complete substitution of Spd by related structures has not been demonstrated.

Intracellular polyamines do not exert toxic effects, as long as physiological regulation by de novo synthesis, uptake, degradation via the interconversion pathway (Seiler, 1987), and release are functional and maintain concentrations within certain limits. However, the prevention of Spm degradation by polyamine oxidase (PAO), an intracellular FAD-dependent enzyme, can be lethal (Sarhan et al., 1991).

If extracellular polyamines undergo oxidative deamination by diamine oxidase, toxic products of this reaction (aldehydes and hydrogen peroxide) cause cell damage and cell death (see, e.g., Sharmin et al., 2001). Direct cytotoxic actions of Spm were observed only at mM concentrations (Brunton et al., 1991, Segal & Skolnick, 2000, Seiler et al., 2000). Neither Spd nor Put is cytotoxic at these concentrations. Spm nephrotoxicity (Rosenthal et al., 1952) was not only a hallmark of polyamine pharmacology but also the starting signal to the systematic investigation of polyamine biochemistry by H. and C.W. Tabor. The fact that Spd and Spm share with aminoglycosides numerous properties (Seiler et al., 1996a) indicates that structural requirements are not stringent as far as toxicological and pharmacological effects are concerned.

About 30 years ago, the inhibition of cell growth due to the selective depletion of Spd has been demonstrated. Spm is not supporting cell growth directly but serves as a precursor of Spd and has, in addition, other functions (Ikeguchi et al., 2004, Wang et al., 2004). The search for inhibitors of polyamine-related enzymes started with the aim to inhibit tumor growth. Selective inhibitors of the enzymes involved in polyamine biosynthesis did not result in practically useful anticancer drugs (Marton & Pegg, 1995, Seiler, 2003a), but a selective inactivator of ornithine decarboxylase, (d,l)-2-(difluoromethyl)ornithine (DFMO), became important in the treatment of African trypanosomiasis (Schechter et al., 1987). It is presently developed as a cancer chemopreventive agent (Gerner & Meyskens, 2004).

Following a suggestion of Porter and Sufrin (1986), numerous derivatives and analogues of the natural polyamines have been synthesized with the aim to generate a new type of anticancer drug. The cytotoxicity and antitumor effects of these compounds have been reviewed (see, e.g., Marton & Pegg, 1995, Kramer, 1996, Seiler, 2003b).

The systematic exploration of structure–activity relationships demonstrated that an enhanced lipophilicity is a common feature of cytotoxic polyamine derivatives and homologs with aliphatic substituents. Hydrophobic interactions affect the pharmacokinetic and pharmacodynamic properties of the compounds due to the increase of binding energy to target macromolecules with anionic binding sites.

Some interest in the pharmacological actions of the natural polyamines has persisted over the decades; however, because of the absence of any therapeutic interest, polyamine pharmacology remained a neglected area (Seiler, 1991) until the activation of the N-methyl-d-aspartate (NMDA) receptor complex by Spm was recognized (Ransom & Stec, 1988). Following its release from necrotic cells, Spm activates glutamic acid excitotoxicity and contributes to neuronal degeneration in ischemia and brain damage. The role of polyamines in cerebral ischemia became an important topic (see, e.g., Johnsson, 1998).

Among the several reasons for the modest success of polyamine derivatives in anticancer therapy, one, is that pharmacological consequences of modifications of the polyamine structure were not well understood. A better knowledge of polyamine analogue pharmacology at an early state of drug development would aid in selecting the most appropriate compounds for drug development.

Section snippets

Major structural types

In addition to the increase in the number of positively charged amino groups, alkyl substituents attached to the amino groups of Put, Spd, and Spm cause an increase in cytotoxicity (Porter et al., 1985, Bergeron et al., 1994; Table 1). Cytotoxicity increases with the number of carbon atoms of the substituents, as is shown for the homospermine derivatives in Table 2. Elongation of the carbon chain between the protonated amino groups has the same effect. This is suggested by the increase in

Some toxicological properties of the polyamines and their derivatives

One of the most conspicuous CNS effects of polyamines is the lowering of body temperature. The mechanism of body temperature regulation by polyamines is still terra incognita. Presumably, they interact directly with the hypothalamic thermoregulatory center. Fig. 2 shows the effect of a series of dimethylsilane tetramines on the body temperature of mice. N-ethylation, that is, increase in lipophilicity, had a particularly great effect (Seiler et al., 1997).

Acute toxicity of the natural

Polyamines as receptor ligands

Although the spontaneous and evoked release of Spm from brain slices has been demonstrated, a neurotransmitter function of the natural polyamines is unlikely. There is, however, evidence for effects on enzyme and receptor proteins, the impairment of neurotransmitter uptake, and on movements of Ca2+ and other cations in neurons, suggesting a modulatory role in numerous brain functions (Seiler, 1991, Carter, 1994, Shaw, 1994).

When studying binding to rat brain membranes, Goodnow et al. (1991)

Structural considerations

The structural requirements for binding to amine binding sites of the NMDA receptors are not stringent. In agreement with many other properties, which these 2 classes of biogenic polycations share (Seiler et al., 1996a), the stimulatory and inhibitory properties of aminoglycoside antibiotics are similar to those of Spm and Spd, although some differences were noticed. Stimulation paralleled the number of amino groups, and stimulation was observed in both glycine-dependent and glycine-independent

The polyamine backbone, a universal template for the development of receptor ligands?

The role of NMDA receptors in long-term potentiation (LTP) is well established. Most natural wasp and spider toxins inhibit the induction of LTP at the collateral CA1 pyramidal cell synapse of the hippocampus through NMDA receptor antagonism. The fact that several synthetic argiotoxin, jorotoxin, and philantotoxin analogues were found to have no effect on LTP induction (Albensi et al., 2000) suggests that it is possible to design receptor selective polyamine analogues by appropriate

Metabolic, toxicologic, and pharmacokinetic properties of N1,N11-diethylnorspermine and N1,N14-diethylhomospermine in experimental animals and humans

The interpretation of pharmacological data obtained from in vivo experiments is, in the case of polyamines and their analogues, hampered, because metabolite formation cannot be excluded. Doyle and Shaw (1994) reported, for example, a reduced neurotoxicity of Spd following pretreatment of mice with MDL 72527. Unfortunately, the efficacy of DENSpm and of related inducers of SAT has not been studied in animal tumor models in the presence of a PAO inhibitor.

DENSpm (Fig. 8) and N1,N14

Attempts to decrease CNS toxicity of polyamine analogues

Although a number of factors affect blood barrier transport, as a rule, an improved blood–brain barrier penetration parallels an increase in lipophilicity (Ecker & Noe, 2004).

The fact that DENSpm showed unusual CNS toxicity in phase I studies catalyzed attempts to decrease the lipophilicity of polyamine analogues by introducing hydroxyl groups (Bergeron et al., 2000a, Bergeron et al., 2001a). In Fig. 9, the structures of 2 tetramines of a series of homologous compounds are shown. The biological

Conclusions

It has repeatedly been mentioned that the incorporation even of a single additional CH2 group into the backbone of a polyamine-like structure measurably affects pharmacological and toxicological properties due to the increase in binding energy. The enormous effect of minor changes demonstrates the stringency of structural requirements for physiological functions of the natural polyamines. Spd and Spm are polycations with a uniquely balanced hydrophilicity/hydrophobicity that allows them to

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