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Fig. 9. Structures of oligamines and macrocyclic polyamines with antitumor activity.

Fig. 9. Structures of oligamines and macrocyclic polyamines with antitumor activity.

(i.e., SL-11121 and SL-11128, Fig. 8) also affords analogs that are equipotent to BE-4444 with respect to ID50 values, but that are an order of magnitude more cytotoxic in a dose-response study (49).

Recently, a series of ,Ws(ethyl)oligamine analogs have been described that show promise as potential chemotherapeutic agents. In the limited series of oligamines that were evaluated, the decamine SL-11144 and the octamine SL-11158 (Fig. 9) proved to be most growth inhibitory against a panel of prostate tumor cells in vitro (LnCap, DU-145, DuPro, and PC-3). Not surprisingly, their activity roughly correlated with their ability to aggregate DNA (56). It has been shown that macrocyclic polyamines known as budmunchiamines act as potent antitumor agents by virtue of their ability to selectively deplete adenosine triphosphate. Based on this observation, a series of five macrocyclic polyamines with the representative structure shown in Fig. 9 were synthesized and evaluated as antitumor agents in the DuPro and PC-3 prostate cell lines (51). All five of these analogs were readily imported by cells and caused a dramatic depletion of cellular polyamines. These compounds also proved to be cytotoxic in the tumor lines tested, and the degree of cytotoxicity roughly correlated to their ability to deplete adenosine triphosphate.

One unusual characteristic of the 6is(ethyl)polyamines is their ability to produce cell type-specific cytotoxicity in two representative lung cancer cell types, NCI H157 non-SCLC and H82 SCLC. Soon after the first alkylpolkyamines were described, it was shown that the 6is(ethyl)polyamines were cytotoxic to DFMO-resistant H157 cells (29) that are clinically characterized as being refractory to all treatment modalities. By contrast, the 6is(ethyl)polyamines are relatively ineffective against DFMO-sensitive SCLC lines. The mechanisms underlying the observed differential sensitivities are still being elucidated, but it was noted that unusually high induction of SSAT (in some cases

>1000 fold) in cell types that respond to Ms(ethyl)polyamine analogs, but not in the refractory cell lines, and a lack of SSAT induction in the refractory SCLC line H82 (15,29). In H157 cells in culture, the induction of SSAT correlated with a time- and dose-dependent increase in SSAT steady-state messenger RNA levels, suggesting a transcriptional level of control over SSAT synthesis. The correlation between high induction of the SSAT activity and cytotoxicity was subsequently demonstrated for other examples of human malignancies, including human melanomas.

2.2. Unsymmetrically Substituted Alkylpolyamine Analogs

Structure activity studies involving the Ms(ethyl)polyamines revealed much about the role of charge and flexibility in the polyamine backbone structure. However, the most useful compounds were symmetrically substituted with ethyl groups at the terminal nitrogens, and it was concluded that substituents of greater size than ethyl would render a molecule inactive. It was clear that unsymmetrically substituted alkylpolyamines needed to be synthesized to determine the optimal substituent pattern for the terminal nitrogens, and to explore the chemical space surrounding the terminal alkyl groups. Compounds that possessed unsymmetrically substituted terminal nitrogens were first described in 1993 (52), the first of which being A^-propargyl-A^-ethylnorspermine (PENSpm) and A1-cyclopropylmethyl-A11-ethylnorspermine (CPENSpm), which are shown in Fig. 10. In general, the synthesis of these and other unsymmetrically substituted analogs is more difficult because it requires selective protection and deprotection of the internal and external nitrogens. Preliminary results indicated that both PENSpm (IC50 = 1.1 |iM) and CPENSpm (IC50 = 1.1 |iM) were as active or more active than BESpm, both with respect to SSAT induction and cytotoxicity in H157 cells in culture. These analogs also retained the cell type-specific cytotoxic activity observed after treatment with BESpm, and their activity was directly correlated to their ability to induce SSAT. This increase in SSAT activity was accompanied by a cell-specific increase in steady-state SSAT messenger RNA that was similar in magnitude to that observed after treatment of the H157 cells with BESpm or BENSpm. These data suggest a similar mechanism of induction of SSAT for these compounds, and supported the hypothesis that there may be a functional relationship between cytotoxicity and SSAT induction in the non-SCLC and SCLC cell lines. A third compound in this series, A1-cycloheptylmethyl-A11-ethylnorspermine (CHENSpm, Fig. 10), was subsequently synthesized and evaluated (4) and was found to retain antitumor activity (IC50 = 0.25 |xM against non-SCLC cells) while producing a less-pronounced cell type-specificity. However, when the induction of SSAT and polyamine levels in the H157 cell line were measured, the analog showed striking differences from the parent analog BESpm. Treatment of H157 cells with 10 |iM BESpm depleted the natural polyamines to undetectable levels and produced a 2849-fold increase in SSAT activity. Under these conditions, the only polyamine that was present in the cell in significant amounts was the analog itself, a response that is typical among SSAT-inducing alkylpolyamines. Surprisingly, treatment with 10 |iM CHENSpm had almost no effect on the levels of putrescine, spermidine, and spermine, and caused only a 15-fold induction of SSAT activity (4). These data suggested that the cytotoxic effects produced by BENSpm,

Fig. 10. The unsymmetrically substituted alkylpolyamines PENSpm, CPENSpm, CBENSpm, CPENTSpm, CHEXENSpm, CHENSpm, and IPENSpm.

PENSpm, and CPENSpm in H157 cells could be mediated by different cellular mechanisms than the effects produced by CHENSpm. In response to these findings, three additional compounds were synthesized that possessed substituents containing the intervening ring sizes (CBENSpm, CPENTSpm, and CHEXENSpm), as shown in Fig. 10. All three analogs were generally cytotoxic in both the H157 and H82 cell lines, but there was no correlation between the induction of SSAT and the IC50 value in the H157 line, as shown in Fig. 11. In this cycloalkyl series, the induction of SSAT decreased dramatically as a function of ring size, whereas the IC50 values were remarkably constant (0.4-0.7 |iM). These data clearly support the contention that there are at least two mechanisms by which unsymmetrically substituted alkylpolyamines produce cytotoxi-city in H157 non-SCLC cells.

Based on data obtained for unsymmetrically substituted alkylpolyamine analogs, it is evident that the structure/activity relationships (SAR) of these polyamine analogs is

H157 Cells
Fig. 11. 96 h SSAT induction and IC50 values in the NCI H157 cell line for selected alkylpolyamine analogs.

more complex than originally postulated. Optimal activity is obtained from molecules that possess secondary terminal nitrogens, but only one of the two terminal nitrogens of the backbone need be substituted with a small alkyl group. Structurally similar compounds, like CPENSpm and CHENSpm, which differ only in the number of carbons in the cycloalkyl substituents, appear to inhibit cell growth by completely different mechanisms. It has also been noted that compounds that significantly induce SSAT tend to be more cell type-specific in their activity than those that do not (4).

In addition to the lung cancer model, unsymmetrically substituted polyamine analogs have been evaluated in prostate cancer model systems (53). CPENSpm and CHENSpm were cytotoxic to the DU145 cell line at concentrations >1 |iM with significant accumulation of each analog, and CHENSpm was found to be cytotoxic to the DU145, PC-3, and LnCap cell lines at 30 |iM. Although the effects of these analogs on the polyamine metabolic pathway appear to be modest in the prostate lines, the cyto-toxicity produced in these cells at low concentrations encourages further study.

The data outlined here suggest that unsymmetrically substituted alkylpolyamines can exhibit varying degrees of SSAT induction based on the size of their terminal alkyl substituents. The SAR model for unsymmetrically substituted alkylpolyamines that superinduce SSAT is shown in Fig. 12A (4). Analogs in this subclass generally possess a 3-3-3 or 3-4-3 carbon skeleton and a Ms(alkyl) substitution pattern on the terminal nitrogens. Unsymmetrically substituted analogs induce as well or better than the parent analogs BESpm and BENSpm. When R1 is ethyl, R2 can vary in size from small (e.g., ethyl, cyclopropylmethyl) to medium size; however, the size of only one of the substituents can be increased beyond ethyl. The central nitrogens are separated by 5.0-5.8 A,

Fig. 12. SAR models for alkylpolyamine analogs. (A) SSAT induction-dependent antitumor agents. (B) SSAT induction-dependent alkylpolyamine antitumor agents and antiparasitic agents.

and each terminal nitrogen is 5.0 A from the adjacent central nitrogen. The binding pocket for Ri will accept only a small alkyl group, whereas the R2 binding pocket can accommodate medium sized groups up to the size of cyclopentylmethyl. Both sper-mine and spermidine analogs can bind to this site, because both types of analogs are capable of superinducing SSAT. The cytotoxicity of agents that fit these criteria can be directly related to the superinduction of SSAT.

The model for the design of SSAT induction-independent alkylpolyamine analogs is shown in Fig. 12B (4). The requirement for Ms(alkyl) substitution remains, but the binding pockets for Ri and R2 seem to be less restrictive. The most active analogs have a small (ethyl) or medium sized Ri and a large R2 (e.g., cycloheptylmethyl or cyclo-hexylmethyl). It is required that one of the alkyl groups must be small (e.g., ethyl) whereas the other must be larger than cyclopentylmethyl. Agents with two large terminal alkyl substituents may possess activity, but are not likely to superinduce SSAT. Active analogs with a 3-3-3 and with a 3-7-3 carbon skeleton have been identified, indicating that active compounds may be synthesized with n varying between 1 and 5. Thus the requirement for the intermediate chain seems to be less restrictive than in the SSAT inducer series. However, steric bulk on the intermediate chain is not well tolerated. These data suggest an effector site which has internal anionic sites between 5 and 10 A apart, and terminal anionic sites that are roughly 5 A away from the respective internal anionic sites. The data suggest that agents that fit these criteria produce cyto-toxicity through an as yet undetermined pathway. It has also been noted that analogs with a 3-7-3 architecture can act as antiparasitic agents, a topic that is beyond the scope of this chapter.

3. Mechanisms for Alkylpolyamine-Induced Cytoxicity

It is clear that alkylpolyamines are capable of producing rapid cytotoxicity in lung and prostate tumor cell lines, but the mechanistic aspects of these effects must still be fully elucidated. However, the induction of programmed cell death (PCD) appears to be a common result after treatment with alkylpolyamines from both structural classes mentioned previously. This effect was first observed in the MCF-7 and MDA-MB-468 breast cancer lines, and later in the H-157 non-SCLC human lung tumor cell line after treatment with CPENSpm (54). In the case of the breast cancer lines, greater than 90% growth inhibition was observed after prolonged treatment with CPENSpm in each of six cell lines tested. The IC50 values for inhibition by CPENSpm in these six breast tumor lines ranged from 0.2 to 1.3 |iM In the breast cancer lines MCF-7 and MDA-468, high molecular weight DNA fragmentation and formation of oligonucleosomal-sized fragments were observed as early as 72 h at a 10 |iM concentration and after 96 h with as little as 1 |iM. Similar results were observed in other breast cancer lines including: T47D, Zr-75-1, MDA 231, and Hs578t. In the case of the NCI H157 lung cancer model, PCD was found to occur at earlier exposure times than observed in the breast tumor lines (53). High molecular weight (>50 kbp) DNA fragmentation was observed after 24 h exposure to 10 |iM CPENSpm. Similar results were observed with 10 |iM BENSpm, but only after 48 h, although the initiation of PCD in Chinese hamster ovary (CHO) cells is quite rapid at high concentrations of the analog (4). Although these results clearly indicate that the unsymmetrically substituted analogs induce PCD, the underlying cellular mechanism(s) had not been elucidated.

Acetylation and subsequent oxidation of polyamines by the SSAT/ PAO pathway is known to produce H2O2 as a byproduct. During superinduction of SSAT, PCD produced by CPENSpm in H157 cells may result from oxidative stress resulting from H2O2 overproduction. When catalase is added in combination with CPENSpm, high molecular weight DNA fragmentation and early fragmentation of the nuclei are greatly reduced (55). Inhibition of PAO by the specific inhibitor A^_A/-Ms(2,3-butadienyl)-1,4-butane-diamine (MDL 72527) resulted in a significant reduction in the formation of high molecular weight DNA, and similarly reduced the number of apoptotic nuclei formed after CPENSpm treatment. These results strongly suggest that H2O2 production by PAO has a role in compound CPENSpm-induced cytotoxicity in H157 cells. Catalase or MDL 72527 had no effect on the formation of high molecular weight DNA fragments or apoptotic bodies when coadministered with CHENSpm, supporting the contention that CPENSpm and CHENSpm produce apoptosis by different mechanisms. Treatment of wild-type H157 cells with both CPENSpm and CHENSpm leads to the activation of caspase-3 and cleavage of poly (adenosine 5'-diphosphate-ribose) polymerase (4). In H157 cells that overexpress Bcl-2, many of the known steps of the cell death program, including caspase-3 activation, poly (adenosine 5'-diphosphate-ribose) polymerase cleavage, and the release of cytochrome c from the mitochondria, were blocked in analog-treated H157 cells. However, the overexpression of Bcl-2 was only able to alter the kinetics of PCD, not completely block it. Thus, both CPENSpm and CHENSpm are capable of inducing PCD in a caspase-3-independent manner.

Several groups have demonstrated that some polyamine analogs (e.g., BE-4444, CHENSpm) that do not superinduce SSAT can still produce PCD. Consistent with this hypothesis is the observation that CPENSpm and CHENSpm have dramatically different effects on the cell cycle (56). After 24 h treatment of H157 non-SCLC with 10 |iM CPENSpm, no significant effects on cell cycle are observed by flow cytometric analysis. However, under the same conditions, 10 |iMCHENSpm produces a dramatic G2/M cell cycle block in normal and Bcl-2-overexpressing H157 cells (4). The analog 5-1-{ Ai-[(2-methyl)-1-butyl]amino}-11-[A'-(ethyl)amino]-4,8-diazaundecane (IPENSpm;Fig. 10) was subsequently found to produce a similar G2/M cell-cycle arrest (57). All three analogs demonstrated similar cytotoxic effects in the human non-SCLC line, NCI H157, where they were found to be cytotoxic at concentrations greater than 0.1 |iM, but significant induction of SSAT activity was only observed in cells treated with CPENSpm. The effects of all three compounds on the cell cycle progress were analyzed by flow cytometry after a 24-h exposure to 10 |iM of each compound. As previously observed, CPENSpm treatment had no significant effect on the cell cycle. However, both CPENSpm and IPENSpm produced a significant G2/M cell-cycle arrest and a concurrent decrease in the G1 fraction. All three analogs, as well as the natural tetraamine, spermine, stimulate tubulin polymerization in the absence of microtubule-associated proteins and other polymerization stimulants, and the rate of polymerization was greatest in the case of CHENSpm (4.9 times faster than spermine). In the presence of microtubule-associated protein-rich tubulin, CHENSpm remained the most effective promoter of tubulin polymerization, whereas CPENSpm and spermine showed significant decreases in their ability to effect tubulin polymerization. These data suggest that CPENSpm, but not CHENSpm, are possibly competing for binding at the site normally occupied by microtubule-associated proteins.

The symmetrically and unsymmetrically substituted alkylpolyamines described have been of great value in determining the mechanisms of analog-induced cytotoxicity. However, the alkyl substituents in these molecules are representative of only a minute portion of the available chemical diversity for the terminal alkyl substituents. Recently, more than 200 alkylpolyamines have been synthesized and evaluated as antitumor agents in an effort to refine the SAR model described in Fig. 12. Preliminary biological evaluation of these analogs was conducted using a high-throughput screen based on 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT cell) viability determination in NCI H157 lung tumor cells. The structures of several of these analogs that demonstrate new structural directions to exploit are shown in Fig. 13, along with their IC50 values in the MTT high-throughput screen. The compounds designated 39-TDW-47C, 39-TDW-12C, and 46-TDW-34C were selected for in vivo studies in an A549 lung tumor xenograft model. Preliminary studies indicate that all three of these analogs are effective in limiting tumor growth in the xenograft model. It is important to note that the compounds shown in Fig. 13 contain structural features that have not previously been included in polyamine analogs described. The data indicate that it is possible to synthesize active alkylpolyamines that contain aralkyl substituents, heteroatoms,

Fig. 13. Novel, structurally diverse alkylpolyamine analogs.

and unsaturations in the terminal alkyl substituents. Additional analogs in this series are being synthesized and used to determine the structural requirements for binding at the various alkylpolyamine effector sites.

4. Future Directions for Polyamine Drug Discovery

As recently as 20 yr ago, the polyamine biosynthetic pathway was still being elucidated and the enzymes were being characterized. Drug discovery efforts were focused on finding specific inhibitors for these enzymes and at determining the cellular consequences of selective depletion of individual polyamines. The polyamine metabolic pathway is now well defined, the enzymes have been characterized, cloned, and expressed in bacterial vectors, and, in the case of AdoMet-DC, the crystal structure of the enzyme is known (58). These research advances have resulted in one marketed agent (i.e., DFMO), two agents that were not developed because of the economic status of the target population

(AbeAdo, MDL 27695), and two or three agents that have the potential will be marketed, and have been or will be studied in human clinical trials as antitumor or antidiar-rheal agents (BENSpm, bis(ethyl)-4444 and BEHSpm). More recent data suggest that some of the antitumor effects attributed to alkylpolyamines are mediated at sites that are independent of the metabolic enzymes. In terms of drug discovery and development, there are multiple avenues through which polyamine analogs may prove to be useful therapeutic agents. Inhibition of the transport system, which mediates both influx and efflux of polyamines from the cell, may prove to be a more reliable way to disrupt polyamine metabolism than selective inhibition of the individual metabolic enzymes. There are a variety of new polyamine-protein binding interactions (e.g., nuclear factor kB, p53 gene expression, the c-myc pathway, expression of caspase-3) that could be validated as targets for novel polyamine-based antitumor agents. Such interactions could be viewed as targets for polyamine analogs that are either chemotherapeutic or chemopreventative. As these targets are refined and validated, second-generation agents that target the functions of the natural polyamines can be rationally designed to bind to these nonenzymatic polyamine binding sites. During the next few years, many research groups will be working toward defining these targets and developing agents that specifically bind to these sites and modulate their function. Although this chapter focuses on the use of polyamine analogs as antitumor agents, there are a number of groups developing analogs that target other known polyamine functions (e.g., analog binding to the N-methyl-D-aspartate (NMDA) receptor, polyamine analogs as antiparasitic agents, polyamines as vectors for gene and drug delivery). The ubiquitous nature of the polyamines, and the wide variety of effects they produce, virtually guarantees that new polyamine effector sites will be discovered, and that these sites will provide new avenues for drug design and development.

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