- PYRROLOQUINAZOLINE COMPOUNDS
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Disclosed herein are acylated derivatives of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and pharmaceutical compositions comprising said derivatives.
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Page/Page column 14-16
(2015/01/07)
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- Discovery of a potent anti-tumor agent through regioselective mono-N-acylation of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine
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7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (1) is a privileged chemical scaffold with significant biological activities. However, the currently accessible chemical space derived from 1 is rather limited. Here we expanded the chemical space related to 1 by developing efficient methods for regioselective monoacylation at N1, N3 and N7, respectively. With this novel methodology, a focused library of mono-N-acylated pyrroloquinazoline-1,3-diamines was prepared and screened for anti-breast cancer activity. The structure-activity relationship (SAR) results showed that N 3-acylated compounds were in general more potent than N 1-acylated compounds while N7-acylation significantly reduced their solubility. Among the compounds evaluated, 7f possessed 8-fold more potent activity than 1 in MDA-MB-468 cells. More importantly, 7f was not toxic to normal human cells. These results suggest that 7f is a novel compound as a potential anti-breast cancer agent without harming normal cells. The Royal Society of Chemistry.
- Chen, Jingjin,Kassenbrock, Alina,Li, Bingbing X.,Xiao, Xiangshu
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supporting information
p. 1275 - 1282
(2013/09/12)
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- High-affinity inhibitors of dihydrofolate reductase: Antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size
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A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by a GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with K(i) values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue. The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans.
- Kuyper, Lee F.,Baccanari, David P.,Jones, Michael L.,Hunter, Robert N.,Tansik, Robert L.,Joyner, Suzanne S.,Boytos, Christine M.,Rudolph, Sharon K.,Knick, Vince,Wilson, H. Robert,Caddell, J. Marc,Friedman, Henry S.,Comley, John C. W.,Stables, Jeremy N.
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p. 892 - 903
(2007/10/03)
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- Lewis Acid Assisted Cyclization of Arylcyanoguanidines to 2,4-Diaminoquinazolines
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The mild preparation of N-cyano-N'-(1-H-indol-5-yl)guanidine and its cyclization to 1,3-diamino-7H-pyrroloquinazoline is described.Whereas previously reported methods of cyclization employed high temperatures to effect ring closure, we found that certain Lewis acids, such as boron trifluoride etherate, induce cyclization at moderate temperatures.
- Jones, Michael L.,Kuyper, Lee F.,Styles, Virgil L.,Caddell, J. Marc
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p. 1681 - 1684
(2007/10/02)
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- 7-(Substituted)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamines
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7-(Substituted)-pyrrolo[3,2-f]quinazoline-1,3-diamines possess antibacterial activity in vitro. The invention also provides compounds having in vivo activity against malarial infections.
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- 7-(Substituted)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamines
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7-(Substituted)-pyrrolo[3,2-f]-quinazoline-1,3-diamines possess antibacterial activity in vitro. The invention also provides compounds having synergism in vivo with sulfa drugs against bacterial infections.
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