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A novel series of alkyl-or aralkyl-substituted polyamine analogues was synthesized containing a 3-7-3 polyamine backbone. These analogues were evaluated in vitro, and in one case in vivo, for activity as antitrypanosomal agents, and for activity against opportunistic infection caused by Microsporidia. Compound 21 inhibits trypanosomal growth with an IC 50 as low as 31 nM, while compound 24 shows promising activity in vitro against trypanosomes, and against Microsporidia in vitro and in vivo.There is no doubt that significant advancements in anti-infective therapy have improved the quality of life in developed nations. However, in underdeveloped countries, there exist major infectious diseases that account for a large portion of global morbidity. Some of these diseases have the potential to become a threat to those living in North America. Tuberculosis claims an estimated 2 million lives each year, and drug-resistant strains originally found in New York and Russia are now being identified in other locations. Malaria, African trypanosomiasis and Leishmaniasis accounted for an additional 1,210,000 deaths in 1999. 1 Also of concern is the increasing incidence of opportunistic infections such as those caused by Pneumocystis carinii and strains of Microsporidia. Drug discovery efforts against the diseases mentioned above are limited because infected persons in underdeveloped areas cannot afford even a single course of therapy, or because the infected population represents too small of a drug market. Clearly, there is a need for new antiinfective agents that are potent, nontoxic and inexpensive to manufacture. We recently described the synthesis and evaluation of a small series of (bis)alkylated polyamines that possess promising antitrypanosomal effects in vitro. 2 Analogues possessing a 3-3-3 carbon skeleton (Fig. 1), such as BENSpm 1, CPENSpm 2, and CHENSpm 3 2,3 have significant antitumor effects in vitro and in vivo, but are inactive against cultured trypanosomes. By contrast, analogues with a 3-7-3-carbon skeleton, typified by MDL 27695 4, 4 CHE-3-7-3 5, 2,3 and bis-CH-3-7-3 6 2,3 are inactive as antitumor agents, but possess promising antitrypanosomal effects in vitro. We now report second generation compounds in the 3-7-3 series, their biological evaluation as anti-trypanosomal agents, and their activity against Microsporidia in vitro and in vivo. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2011 June 7. ChemistryThe syntheses leading to (bis)alkylated polyamines, which are outlined in Scheme 1, are facile and straight-forward, and as such are suitable for the efficient and cost-effective production of a variety of active analogues. The tetraamine 7 can be readily synthesized from 1,3-bis-[(amino)methyl]cyclohexane in three steps. 2 Cyanoethylation 5 followed by Raney nickel reduction 5 of the cyano groups affords the corresponding tetraamine in high yield, which is then tetramesitylated (2-mesitylenesulfonyl chloride, dichloromethane, 10% aqueous NaOH) 6...

Polyamine analogues such as bis(ethyl)norspermine and N1-(cyclopropylmethyl)-N11-ethyl-4,8-diazaundecane (CPENSpm) act as potent modulators of cellular polyamine metabolism in vitro and possess impressive antitumor activity against a number of cell lines. Some of these polyamine analogues appear to produce their cell-type-specific cytotoxic activity through the superinduction of spermidine/spermine N1-acetyltransferase (SSAT). However, there are several analogues (e.g., N1-(cycloheptylmethyl)-N11-ethyl-4, 8-diazaundecane (CHENSpm)) which are effective cytotoxic agents but do not superinduce SSAT. We have previously demonstrated that CPENSpm and CHENSpm both initiate the cell death program, although by different mechanisms, and that CHENSpm (but not CPENSpm) induces a G2/M cell cycle arrest. We now report that one potential mechanism by which some polyamine analogues can retard growth and ultimately produce cytotoxicity is through interference with normal tubulin polymerization. In these studies, we compare the effects of the polyamine analogues CHENSpm, CPENSpm, and (S)-N1-(2-methyl-1-butyl)-N11-ethyl-4,8-diazaundecane (IPENSpm) on in vitro tubulin polymerization. These spermine analogues behave very differently from spermine and from each other in terms of tubulin polymerization rate, equilibrium levels, and time of polymerization initiation. These results demonstrate that structurally similar polyamine analogues with potent antitumor effects can produce significantly different cellular effects. The discovery of polyamine analogues that can alter tubulin polymerization provides a series of promising lead compounds that may have a similar spectrum of activity to more difficult to synthesize compounds typified by paclitaxel.

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