82484-59-1Relevant academic research and scientific papers
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
, 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.
The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker
Marvania, Bhavin,Kakadiya, Rajesh,Christian, Wilson,Chen, Tai-Lin,Wu, Ming-Hsi,Suman, Sharda,Tala, Kiran,Lee, Te-Chang,Shah, Anamik,Su, Tsann-Long
, p. 695 - 708 (2014/07/22)
We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure-activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a-o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a-d) in inhibiting the cell growth of various human tumor cell lines in vitro. However, the methylamino or aniline substituents at C4 of quinoline did not influence the cytotoxic effects. The title conjugates were capable of inducing DNA cross-linking and promoting cell-cycle arrest at the G2/M phase. This study demonstrates that phenyl N-mustard-4-anilinoquinoline conjugates are generally more potent than phenyl N-mustard-4-anilinoquinazoline conjugates against the cell growth of various tumor cell-lines.
Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents
Kapuriya, Naval,Kakadiya, Rajesh,Dong, Huajin,Kumar, Amit,Lee, Pei-Chih,Zhang, Xiuguo,Chou, Ting-Chao,Lee, Te-Chang,Chen, Ching-Huang,Lam, King,Marvania, Bhavin,Shah, Anamik,Su, Tsann-Long
experimental part, p. 471 - 485 (2011/02/27)
A series of novel water-soluble N-mustard-benzene conjugates bearing a urea linker were synthesized. The benzene moiety contains various hydrophilic side chains are linked to the meta- or para-position of the urea linker via a carboxamide or an ether link
Design, synthesis and antitumor evaluation of phenyl N-mustard-quinazoline conjugates
Marvania, Bhavin,Lee, Pei-Chih,Chaniyara, Ravi,Dong, Huajin,Suman, Sharda,Kakadiya, Rajesh,Chou, Ting-Chao,Lee, Te-Chang,Shah, Anamik,Su, Tsann-Long
scheme or table, p. 1987 - 1998 (2011/04/25)
A series of N-mustard-quinazoline conjugates was synthesized and subjected to antitumor studies. The N-mustard pharmacophore was attached at the C-6 of the 4-anilinoquinazolines via a urea linker. To study the structure-activity relationships of these conjugates, various substituents were introduced to the C-4 anilino moiety. The preliminary antitumor studies revealed that these agents exhibited significant antitumor activity in inhibiting various human tumor cell growths in vitro. Compounds 21b, 21g, and 21h were selected for further antitumor activity evaluation against human breast carcinoma MX-1 and prostate PC-3 xenograft in animal model. These agents showed 54-75% tumor suppression with low toxicity (5-7% body-weight changes). We also demonstrate that the newly synthesized compounds are able to induce DNA cross-linking through alkaline agarose gel shift assay and inhibited cell cycle arrest at G2/M phase.
Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker
Kakadiya, Rajesh,Dong, Huajin,Kumar, Amit,Narsinh, Dodia,Zhang, Xiuguo,Chou, Ting-Chao,Lee, Te-Chang,Shah, Anamik,Su, Tsann-Long
experimental part, p. 2285 - 2299 (2010/06/14)
A series of N-mustard-quinoline conjugates bearing a urea or hydrazinecarboxamide linker was synthesized for antitumor evaluation. The in vitro cytotoxicity studies revealed that compounds with hydrazinecarboxamide linkers were generally more cytotoxic th
Novel DNA-directed alkylating agents: Design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker
Kapuriya, Naval,Kapuriya, Kalpana,Dong, Huajin,Zhang, Xiuguo,Chou, Ting-Chao,Chen, Yu-Ting,Lee, Te-Chang,Lee, Wen-Chuan,Tsai, Tung-Hu,Naliapara, Yogesh,Su, Tsann-Long
experimental part, p. 1264 - 1275 (2009/07/18)
A series of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker was synthesized for antitumor evaluation. The carbamate or carbonate linker is able to lower the reactivity of the phenyl N-mustard pharmacophore and thus, these
Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage
Kapuriya, Naval,Kapuriya, Kalpana,Zhang, Xiuguo,Chou, Ting-Chao,Kakadiya, Rajesh,Wu, Yu-Tse,Tsai, Tung-Hu,Chen, Yu-Ting,Lee, Te-Chang,Shah, Anamik,Naliapara, Yogesh,Su, Tsann-Long
, p. 5413 - 5423 (2008/12/21)
To improve the chemical stability and therapeutic efficacy of N-mustard, a series of phenyl N-mustard linked to DNA-affinic 9-anilinoacridines and acridine via a urea linker were synthesized and evaluated for antitumor studies. The new N-mustard derivatives were prepared by the reaction of 4-bis(2-chloroethyl)aminophenyl isocyanate with a variety of 9-anilinoacridines or 9-aminoacridine. The antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro without cross-resistance to taxol or vinblastine and showed potent antitumor therapeutic efficacy in nude mice against human tumor xenografts. It also showed that 24d was capable of inducing marked dose-dependent levels of DNA cross-linking by comet assay and has long half-life in rat plasma.
ANILINE OR PHENOL MUSTARDS LINKED TO DNA-AFFINIC MOLECULES OR WATER-SOLUBLE AROMATIC RINGS AND THEIR USE AS CANCER THERAPEUTIC AGENTS
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Page/Page column 17, (2008/12/06)
New aniline or phenol N-mustards linked to DNA-affinity carriers (such as 9-anilinoacridines, acridines andquinolines), aminobenzamides or aminophenol ethers by a urea, carbamic acid, carbanic acid ester, hydxazine urea, hydrazine carbamic acid ester, phenoxyurea, phenoxycarbamic acid ester linkage with improved chemical stability and anti-tumor therapeutic efficacy are provided.
Fluorosulfonyl- and bis-(β-chloroethyl)amino-phenylamino functionalized pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: Irreversible antagonists at the human a3 adenosine receptor and molecular modeling studies
Baraldi,Cacciari,Moro,Romagnoli,Ji,Jacobson,Gessi,Borea,Spalluto
, p. 2735 - 2742 (2007/10/03)
A series of pyrazolotriazolopyrimidines was previously reported to be highly potent and selective human A3 adenosine receptor antagonists (Baraldi et al. J. Med. Chem. 2000, 43, 4768-4780). A derivative having a methyl group at the N8 pyrazole combined with a 4-methoxyphenylcarbamoyl moiety at N5 position, displayed a Ki value at the hA3 receptor of 0.2 nM. We now describe chemically reactive derivatives which act as irreversible inhibitors of this receptor. Electrophilic groups, specifically sulfonyl fluoride and nitrogen mustard (bis-(β-chloroethyl)-amino) moieties, have been incorporated at the 4-position of the aryl urea group. Membranes containing the recombinant hA3 receptor were preincubated with the compounds and washed exhaustively. The loss of ability to bind radioligand following this treatment indicated irreversible binding. The most potent compound in irreversibly binding to the receptor was 14, which contained a sulfonyl fluoride moiety and a propyl group at the N8 pyrazole nitrogen. The bis-(β-chloroethyl)amino derivatives displayed a much smaller degree of irreversible binding than the sulfonyl fluoride derivatives. A computer-generated model of the human A3 receptor was built and analyzed to help interpret these results. The model of the A3 transmembrane region was derived using primary sequence comparison, secondary structure predictions, and three-dimensional homology building, using the recently published crystal structure of rhodopsin as a template. According to our model, sulfonyl fluoride derivatives could dock within the hypothetical TM binding domain, adopting two different energetically favorable conformations. We have identified two amino acids, Ser247 and Cys251, both in TM6, as potential nucleophilic partners of the irreversible binding to the receptor.
Self-immolative nitrogen mustard prodrugs for suicide gene therapy
Niculescu-Duvaz, Dan,Niculescu-Duvaz, Ion,Friedlos, Frank,Martin, Janet,Spooner, Robert,Davies, Lawrence,Marais, Richard,Springer, Caroline J.
, p. 5297 - 5309 (2007/10/03)
Four new potential self-immolative prodrugs derived from phenol and aniline nitrogen mustards, four model compounds derived from their corresponding fluoroethyl analogues and two new self-immolative linkers were designed and synthesized for use in the suicide gene therapy termed GDEPT (gene-directed enzyme prodrug therapy). The self-immolative prodrugs were designed to be activated by the enzyme carboxypeptidase G2 (CPG2) releasing an active drug by a 1,6-elimination mechanism via an unstable intermediate. Thus, N-[(4-{[4-(bis{2- chloroethyl}amino)phenoxycarbonyloxy]methyl}phenyl)carbamoyl]-L-glutamic acid (23), N-[(4-{[4(bis{2- chloroethyl}amino)phenoxycarbonyloxy]methyl}phenoxy)carbonyl]-L-glutamic acid (30), N-[(4-{N-(4-(bis[2- chloroethyl]amino}}pheny)carbamoyloxy]methyl}phenoxy)carbonyl]-L-glutmic acid (37), and N-[(4-{[N-(4-{bis[2- chloroethyl]amino}phenyl)carbamoyloxy]methyl}phenyl)carbamoyl]-L-glutamic acid (40) were synthesized. They are bifunctional alkylating agents in which the activating effects of the phenolic hydroxyl or amino functions are masked through an oxycarbonyl or a carbamoyl bond to a benzylic spacer which is itself]inked to a glutamic acid by an oxycarbonyl or a carbamoyl bond. The corresponding fluoroethyl compounds 25, 32, 42, and 44 were also synthesized. The rationale was to obtain model compounds with greatly reduced alkylating abilities that would be much less reactive with nucleophiles compared to the corresponding chloroethyl derivatives. This enabled studies of these model compounds as substrates for CPG2, without incurring the rapid and complicated decomposition pathways of the chloroethyl derivatives. The prodrugs were desired to be activated to their corresponding phenol and aniline nitrogen mustard drugs by CPG2 for use in GDEPT. The synthesis of the analogous novel parent drugs (21b, 51) is also described. A colorectal cell line was engineered to express CPG2 tethered to the outer cell surface. The phenylenediamine compounds were found to behave as prodrugs, yielding IC50 prodrug/IC50 drug ratios between 20- and 33-fold (for 37 and 40) and differentials of 12-14-fold between CPG2-expressing and control LacZ- expressing clones. The drugs released are up to 70-fold more potent than 4- [(2-chloroethyl)(2-mesyloxyethyl)amino]benzoic acid that results from the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMBA) which has been used previously for GDEPT. These data demonstrate the viability of this strategy and indicate that self-immolative prodrugs can be synthesized to release potent mustard drugs selectively by cells expressing CPG2 tethered to the cell surface in GDEPT.
