854813-63-1Relevant articles and documents
Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach
Tala, Satishkumar D.,Ou, Tai-Hsin,Lin, Yi-Wen,Tala, Kiranben S.,Chao, Shu-Hsin,Wu, Ming-Hsi,Tsai, Tung-Hu,Kakadiya, Rajesh,Suman, Sharda,Chen, Ching-Huang,Lee, Te-Chang,Su, Tsann-Long
supporting information, p. 155 - 169 (2014/03/21)
A series of new, water-soluble phenyl N-mustard-benzenealkylamide conjugates containing hydrophilic ω-dialkylaminoalkylamide or ω-cyclic aminoalkylamide moieties were synthesized via a bioisostere approach. These compounds have a broad spectrum of antitumor activity against a panel of human tumor cell lines. Of these derivatives, compound 18b effectively suppressed the growth of colon cancer (HCT-116), prostate cancer (PC3), and lung cancer (H460) xenografts. The growth of HCT-116 xenografts was almost completely suppressed when co-treated with compound 18b and 5-fluorouracil. Furthermore, compound 18b can induce DNA cross-linking and cell-cycle arrest at the G2/M phase. Early preclinical studies, including pharmacokinetics in rats, inhibition of the hERG, and 14 days of acute intravenous injection toxicity, suggest that compound 18b is a promising candidate for further preclinical studies.
Rational design of substituted diarylureas: A scaffold for binding to G-quadruplex motifs
Drewe, William C.,Nanjunda, Rupesh,Gunaratnam, Mekala,Beltran, Monica,Parkinson, Gary N.,Reszka, Anthony P.,Wilson, W. David,Neidle, Stephen
supporting information; experimental part, p. 7751 - 7767 (2009/12/07)
The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such urea-based ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using short-term cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.
THERAPEUTIC G-QUADRUPLEX LIGANDS
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Page/Page column 21-22, (2008/12/05)
The invention provides compounds of formula (I): wherein Ar1 is a monocyclic aryl or heteroaryl; X and Y are each independe ntly a group of formula (II): Z is absent, a group of formula (II), optionally substituted C1-7 alkyl, optionally substituted C3-20 heterocyclyl, optionally substituted C5-20 aryl, halo, amino, hydroxy, ether, thio, thioet her, carboxy or cyano; L1 and L2 are each independently selected from NR 3, C2H2, CH2, -O-, -S- and a bond; Ar2 and Ar3 are independently optionally substituted C 5 or C6 aryl or heteroaryl; n is an integer from 1 to 5; R1 and R2 are independently hydrog en, C1-7 alkyl, C3-20 heterocyclyl, or C 5-20 aryl, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 3 to 8 ring atoms; R3 is H or C 1-7 alkyl; and provided that at least one of Ar 1, Ar2 and Ar3 is oxazole, triazole or tetrazole. These compounds are thought to bind G -quadruplexes formed in human telomeres and are therefore useful in anti -cancer therapy. The invention also provides pharmaceutical compositions comprising the novel compounds, and methods for their manufacture.
