- Analogs of biologically active, naturally occurring polyamines, pharmaceutical compositions and methods of treatment
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Polyamines having the formula: 1or a salt thereof with a pharmaceutically acceptable acid wherein: R1-R6 may be the same or different and are alkyl, aryl, aryl alkyl, cycloalkyl, optionally having an alkyl chain interrupted by at least one etheric oxygen atom, or hydrogen; N1, N2, N3 and N4 are nitrogen atoms capable of protonation at physiological pH's; a and b may be the same or different and are integers from 1 to 4; A, B and C may be the same or different and are bridging groups which effectively maintain the distance between the nitrogen atoms such that the polyamines: (i) are capable of uptake by a target cell upon administration thereof to a human or non-human animal; and (ii) upon uptake by the target cell, competitively bind via an electrostatic interaction between the positively charged nitrogen atoms to substantially the same biological counter-anions as the intracellular natural polyamines in the target cell; the polyamines, upon binding to the biological counter-anion in the cell, function in a manner biologically different than the intracellular polyamines, the polyamines not occurring in nature; as well as pharmaceutical compositions embodying the polyamines and methods of treating patients requiring anti-neoplastic therapy.
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- Analogs of biologically active, naturally occurring polyamines, pharmaceutical compositions and methods of treatment
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Polyamines having the formula: or a salt thereof with a pharmaceutically acceptable acid wherein: R1-R6may be the same or different and are alkyl, aryl, aryl alkyl, cycloalkyl, optionally having an alkyl chain interrupted by at least
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Page column 15
(2010/01/30)
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- Methods and compositions for the treatment of neurodegeneration
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Methods and pharmaceutical compositions in unit dosage form for treating neurodegeneration in a human or non-human animal afflicted therewith wherein the active agent is a therapeutically effective amount of a polyamine having the formula: STR1 or a salt thereof with a pharmaceutically acceptable acid wherein: R1 and R6 may be the same or different and are hydrogen, alkyl, hydrocarbyl aryl, hydrocarbyl aryl alkyl, cycloalkyl, or any of the foregoing wherein the alkyl chain is interrupted by at least one etheric oxygen atom; N1, N2, N3 and N4 are nitrogen atoms capable of protonation at physiological pH's; a and b may be the same or different and are integers from 1 to 4; A, B and C may be the same or different and are bridging groups of variable length.
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- The Role of Charge in Polyamine Analogue Recognition
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A series of analogues and homologues of N1,N12-diethylspermine (DESPM) was synthesized, and their biological properties were evaluated.These tetraamines include a simple linear analogue of DESPM, N1,N12-bis(2,2,2-trifluoroethyl)spermine (FDESPM), the cyclic analogues of DESPM, N,N'-bis(4-piperidinylmethyl)-1,4-diaminobutane and N,N'-bis-1,4-diaminobutane , and their aromatic counterparts, N,N'-bis(4-pyridylmethyl)-1,4-diaminobutane and N,N'-bis-1,4-diaminobutane .The analogues FDESPM, PIP(4,4,4), and PYR(4,4,4) have distances between their nitrogen atoms almost identical to those of DESPM.The longer analogues PIP(5,4,5) and PYR(5,4,5) are very similar in the spacing of their amino groups.However, the pKa of the nitrogens in the groups differ; thus, the extent of protonation and the charge characteristics among the members of the groups differ.A comparison of the biological properties of these compounds clearly demonstrates that the tetraamines must be charged to be "recognized" by the cell.Analogues with low nitrogen pKa's such that the nitrogens are poorly protonated at physiological pH do not compete well with spermidine for uptake and, as expected, have high 96 h IC50 values and have little effect on S-adenosylmethionine decarboxylase, ornithine decarboxylase, and spermidine/spermine N1-acetyltransferase activities and on intracellular polyamine pools.
- Bergeron, Raymond J.,McManis, James S.,Weimar, William R.,Schreier, Katherine M.,Gao, Fenglan,et al.
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p. 2278 - 2285
(2007/10/02)
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