Metabolically Programmed Polyamine Analogue Antidiarrheals

Abstract

The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N1,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N1,N14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)2-DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have a Ki for polyamine transport essentially identical with that of DEHSPM. The experimentally measured Ki and also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.

Chiral Polyamino Alcohols via Hydroaminomethylation: A New Class of Polyamines for Dendritic Cores and Ligand Precursors

“…[21] Purescine derivatives have been used as antimalaria [22] and antiplasmodic agents. [23] This kind of polyamines has also been found to be important in other fields of current research, for example, metabolism [24] and biogenesis, [25] antibiotics, [26] coagulation inhibitors, [27] antidiarrhoics [28] and cytostatics. [29] The two-step hydroaminomethylation/hydrolysis procedure has been used so far to synthesize chiral amino alcohols with low Mw (Scheme 2 and Scheme 3).…”

A comprehensive view of polyamine and histamine metabolism to the light of new technologies

“…This emergent area of research could be applied for the study of new modulators of histamine and polyamine metabolism with potential pharmaco-logical interest. This is the case of previously described metabolically programmed polyamine analog antidiarrheals [67].…”

Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates

“…[87] It has been shown that certain PA analogues can act, for example, as antiparasitic [88] and antimalarial [89] agents, and as antidiarrhoeals. [90] Thus, DEHSPM is already under clinical evaluation to control chronic diarrhoea, in particular associated with AIDS patients, whereas a new class of metabolically unstable, to avoid accumulation of cytotoxic metabolites, PA antidiarrhoeals (e.g. 38, Figure 10) has been recently developed by Bergeron et al [90] Macrocyclic polyamines, such as the bicyclams IPS31 [91] or JM 3100 ( Figure 10) [92] or their complexes with metals, e.g.…”

“…[90] Thus, DEHSPM is already under clinical evaluation to control chronic diarrhoea, in particular associated with AIDS patients, whereas a new class of metabolically unstable, to avoid accumulation of cytotoxic metabolites, PA antidiarrhoeals (e.g. 38, Figure 10) has been recently developed by Bergeron et al [90] Macrocyclic polyamines, such as the bicyclams IPS31 [91] or JM 3100 ( Figure 10) [92] or their complexes with metals, e.g. IPS32, [91] have been found effective against HIV-1 and HIV-2, acting as fusion inhibitors.…”

“…Thus, Bergeron et al bisalkylated N,NЈ-Bn 2 -PUT with (S)-epichlorohydrin as a key-reaction en route to the development of metabolically labile antidiarrhoeals. [90] …”