52606-01-6Relevant articles and documents
Potent colchicine-site ligands with improved intrinsic solubility by replacement of the 3,4,5-trimethoxyphenyl ring with a 2-methylsulfanyl-6-methoxypyridine ring
Aramburu, Laura,Gajate, Consuelo,Medarde, Manuel,Mollinedo, Faustino,álvarez, Raquel,Peláez, Rafael,Vicente-Blázquez, Alba
, (2020/03/27)
Colchicine site antimitotic agents typically suffer from low aqueous solubilities and are formulated as phosphate prodrugs of phenolic groups. These hydroxyl groups are the aim of metabolic transformations leading to resistance. There is an urgent need for more intrinsically soluble analogues lacking these hydroxyl groups. The 3,4,5-trimethoxyphenyl ring of combretastatin A-4 is a liability in terms of solubility but it is considered essential for high cytotoxic and tubulin polymerization inhibitory (TPI) activity. We have synthesized 36 new analogues of combretastatin A-4 replacing the trimethoxyphenyl moiety with more polar pyridine based moieties, measured their aqueous solubility, and studied their anti-proliferative effects against 3 human cancer cell lines. We show here that pyridine rings can be successful replacements for the trimethoxyphenyl ring, resulting in potent and more soluble analogues. The more straightforward replacement, a 2,6-dimethoxypyridine ring led to inactive analogues, but a 2-methoxy-6-methylsulfanylpyridine moiety led to active analogues when combined with different B rings. This replacement led to potent cytotoxic activity against sensitive human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies. Cell cycle analysis also showed apoptotic responses following treatment. Docking studies suggested binding at the colchicine site of tubulin and provided a good agreement with the observed SAR. A 2-methoxy-6-methylsulfanylpyridine moiety is a good trimethoxyphenyl ring replacement for the development of new colchicine site ligands.
New 2,5-diaryl tetryhydrofurans and analogs thereof as paf antagonists
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, (2008/06/13)
Compounds of formula: are disclosed wherein R and R1 are (a) hydrogen;(b) haloloweralkyl;(c) halo;(d) CONR2R3 wherein R2 and R3 independently represent hydrogen, C1-8 alkyl, or C3-8 cycloalkyl;(e) loweralkenyl;(f)-COR2;(g)-CH?OR2;(h) loweralkynyl;(i)-CH?NR2R3;(j)-CH?SR2;(k) =O; or(l)-OR2;(m)-R2; Ar and Ar1 are (a) phenyl or substituted phenyl of formula where R?-R? independently represent H; R2; YO-wherein Y is loweralkenyl, loweralkynyl,-CH? ,-CH?C(O) OR2,-CH?OR2,-CH?C3-8cycloalkyl,-CH? Ar2 wherein Ar2 is phenyl or substituted phenyl,-CH?-CH(OH)-CH? OH; R2S-(O)n wherein R2 can only be C3-8 cycloalkyl and n is 0 to 2; CF?SO, CF?SO?;-CONR2R3;-NR2COR3;-OCONH?-CR2R3R? wherein R? is the same as or different from R2;-CH?OR2;-CH?CO?R2;-CH?OCOR3;-CH?O-CO-OR2;-NHCH?COOR2; halo; or N?R2R3R?X? wherein X? is an anion;(b) monoheteroaryl, di-or polyheteroaryl or fused heteroaryl containing 1 to 3 of any one or more of the heteroatoms N, S or O;(c) heteroarylalkyl;(d) heterocycloalkyl; or(e) heterocycloalkenyl. These compounds are found to have potent and specific PAF (Platelet Activating Factor) antagonistic activities.