45185-87-3Relevant academic research and scientific papers
Dicationic bis(9-methylphenazine-1-carboxamides): Relationships between biological activity and linker chain structure for a series of potent topoisomerase targeted anticancer drugs
Gamage,Spicer,Finlay,Stewart,Charlton,Baguley,Denny
, p. 1407 - 1415 (2001)
Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH2)nNR(CH2)mNR- (CH2)n linkers of varying length (carboxamide N-N distances from 11.0 to 18.4 ?) and rigidity were prepared by reaction of 9-methylphenazine-1-carboxylic acid imidazolide with the appropriate polyamines. The compounds were evaluated for growth inhibitory properties in P388 leukemia, Lewis lung carcinoma, and wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia with low levels of topoisomerase II (topo II). The compounds all had IC50 ratios of 2)2NR(CH2)2NR (CH2)2 linker were' extremely potent cytotoxins, with selectivity toward the human cell lines, but absolute potencies declined sharply from R = H through R = Me to R = Pr and Bu. In contrast, (CH2)2NR(CH2)3-NR (CH2)2 compounds showed reverse effects, with the R = Me analogue being more potent than the R = H one as well as being the most potent in the series [IC50 in JLC cells 0.08 nM, superior to that for the clinical bis(naphthalimide) LU 79553]. Overall, the IC50s of analogues with linker chains (CH2)nNH(CH2)mNH (CH2)n were inversely proportional to linker length. Constraining the rigidity of the linker chain by incorporating a piperazine ring did not decrease potency significantly. A representative compound bound tightly to DNA with high selectivity for GC sites, compatible with recent work suggesting that compounds of this type place their side chains in the major groove, making specific contacts with guanine bases. Representative compounds were susceptible to transport mediated resistance, being much less effective in cells that overexpressed P-glycoprotein. Overall the results suggest these compounds have a similar mode of action, mediated primarily by poisoning of topo I (possibly with some involvement of topo II). The bis(9-methylphenazine-1-carboxamides) show very high in vitro growth inhibitory potencies compared to their monomeric analogues. Two compounds showed in vivo activity in murine colon 38 syngeneic and HT29 human colon tumor xenograft models using intraperitoneal dosing.
Polyamine analogue regulation of NMDA MK-801 binding: A structure-activity study
Bergeron, Raymond J.,Weimar, William R.,Wu, Qianhong,Feng, Yang,McManis, James S.
, p. 5257 - 5266 (2007/10/03)
A series of analogues and homologues of spermine were synthesized, and their impact on MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor was evaluated. These tetraamines encompass both linear and cyclic compounds. The linear molecules include norspermine, N1,N11-diethylnorspermine, N1,N12-bis(2,2,2-trifluoroethyl)spermine, homospermine, and N1,N14-diethylhomospermine. The cyclic tetraamines consist of the piperidine analogues N1,N3-bis(4-piperidinyl)-1,3-diaminopropane, N1,N4-bis(4-piperidinyl)-1,4-diaminobutane, N1,N4-bis(4-piperidinylmethyl)-1,4-diaminobutane, and N1,N4-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane and the pyridine analogues N1,N3-bis(4-pyridyl)-1,3-diaminopropane, N1,N4-bis(4-pyridyl)-1,4-diaminobutane, N1,N4-bis(4-pyridylmethyl)-1,4-diaminobutane, and N1,N4-bis[2-(4-pyridyl)-ethyl]-1,4-diaminobutane. This structure-activity set makes it possible to establish the importance of charge, intercharge distance, and terminal nitrogen substitution on polyamine-regulated MK-801 binding in the NMDA channel. Four families of tetraamines are included in this set: norspermines, spermines, homospermines, and tetraazaoctadecanes. Calculations employing a SYBYL modeling program revealed that the distance between terminal nitrogens ranges between 12.62 and 19.61 ?. The tetraamines are constructed such that within families cyclics and acyclics have similar lengths but different nitrogen pKa's and thus different protonation, or charge, states at physiological pH. The pKa values for all nitrogens of each molecule and its protonation state at physiological pH are described. The modifications at the terminal nitrogens include introduction of ethyl and β,β,β-trifluoroethyl groups and incorporation into piperidinyl or pyridyl systems. The studies clearly indicate that polyamine length, charge, and terminal nitrogen substitution have a significant effect on how the tetraamine regulates MK-801 binding to the NMDA receptor. Thus a structure-activity basis set on which future design of MK-801 agonists and antagonists can be based is now available.
