- Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy
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The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.
- Matera, Carlo,Gomila, Alexandre M. J.,Camarero, Núria,Libergoli, Michela,Soler, Concepció,Gorostiza, Pau
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- Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diamino-quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium
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The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine (8) and 2,4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[b,f]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was 100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.
- Rosowsky,Fu,Queener
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- PHOTORESPONSIVE COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel photoresponsive compound that is useful as a medicament, or a reagent for analyzing in vivo intermolecular interaction, or the like. SOLUTION: Provided is a compound represented by the following formula (I-1) or (I
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- PHOTOISOMERIZABLE DERIVATIVES OF DIHYDROFOLATE REDUCTASE INHIBITORS
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The present invention relates a compound of formula (I) in Z-isomer form (Z-(l)) or a compound of formula (I) in E-isomer form (E-(l)) wherein: R2 is a radical of formula (II) and of formula (III); X1, X2, X3, X4 and X5 are CR3 and N; Y1 is NH, O and S; each R1, each R3 and R7 are H, halogen, -OH, -O-(C1-C8)alkyl, -N((C1-C8)alkyl)3, -NH((C1-C8)alkyl)2, and -NH2(C1-C8)alkyl; R4, R5 and R6 are H and (C1-C8)alkyl; - - - line indicates the position of R2 radical by which R2 is attached to the adjacent N; and the asterisk indicates a stereogenic carbon atom being in R-isomer, S-isomer and a mixture of R-isomer and S-isomer. It also relates to the compound Z-(l) for use as a medicament; and the compound E-(l) for use in the treatment of a disease or condition mediated by the dihydrofolate reductase, wherein the treatment comprises exposing a compound E-(I) to light irradiation to obtain the compound Z-(l).
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(2019/07/13)
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- Design, synthesis and cytotoxic evaluation of quinazoline-2,4,6-triamine and 2,6-diaminoquinazolin-4(3H)-one derivatives
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A series of quinazoline-2,4,6-triamine (quinazoline) and 2,6-diaminoquinazolin-4(3H)-one (quinazolinone) derivatives were designed, synthesized and evaluated as cytotoxic agents in three cancer cell lines (HCT-15, SKOV-3, and MDA-MB-231) using conventiona
- Matus-Meza, Audifás S.,Velasco-Velázquez, Marco A.,Hernández-Luis, Francisco
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p. 1748 - 1756
(2018/05/26)
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- Acetamides compound and application thereof
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The invention relates to an acetamides compound and application thereof, and discloses an N-(4-substituted phenyl ethyl) amides compound with a novel structure. An in vitro activity test experiment proves that the compound has the enzyme inhibitory activity on cysteine proteinase (FP-2) and dihydrofolate reductase (DHFR); a malaria-killing experiment result proves that the compound has an inhibition effect on wild and drug-resistant malaria protozoon.
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- Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely
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Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50 = 10.0 μM), PfDHFR (IC50 = 84.1 nM), P. falciparum 3D7 (IC50 = 53.1 nM), clinical isolated strains Fab9 (IC50 = 14.2 nM) and GB4 (IC50 = 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.
- Chen, Wenhua,Huang, Zhenghui,Wang, Wanyan,Mao, Fei,Guan, Longfei,Tang, Yun,Jiang, Hualiang,Li, Jian,Huang, Jin,Jiang, Lubin,Zhu, Jin
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p. 6467 - 6478
(2017/10/31)
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- Synthesis and biological evaluation of new glutamic acid-based inhibitors of MurD ligase
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Mur ligases catalyze the biosynthesis of the UDP-MurNAc-pentapeptide precursor of peptidoglycan, an essential polymer of bacterial cell-wall. They constitute attractive targets for the development of novel antibacterial agents. Here we report on the synth
- Tomasic, Tihomir,Zidar, Nace,Rupnik, Veronika,Kovac, Andreja,Blanot, Didier,Gobec, Stanislav,Kikelj, Danijel,Masic, Lucija Peterlin
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p. 153 - 157
(2009/05/07)
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- N9-substituted 2,4-diaminoquinazolines: Synthesis and biological evaluation of lipophilic inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase
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N9-substituted 2,4-diaminoquinazolines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). Reduction of commercially available 2,4-diamino-6- nitroquinazoline 14 with Raney n
- Gangjee, Aleem,Adair, Ona O.,Pagley, Michelle,Queener, Sherry F.
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body text
p. 6195 - 6200
(2009/10/01)
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- Process for synthesizing antifolates
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A process for synthesizing antifolate compounds is disclosed. The process includes cyclization of a readily available starting reagent, followed by one or more coupling steps to produce compounds that mimic folic acid. The compounds synthesized have commercial use as drugs in oncology, inflammatory disease, and other medical fields.
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- Thrombin inhibitors
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The invention relates to compounds of formula I D—CO—B—A-Het and pharmaceutically acceptable salts thereof where substituents in description have the specified meanings. The compounds are used as thrombin inhibitors.
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(2010/01/31)
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- Synthesis and enzymatic hydrolysis of esters, constituting simple models of soft drugs
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One way to minimise systemic side effects of drugs is to design molecules, soft drugs, in such a way that they are metabolically inactivated rapidly after having acted on their pharmacological target. Hydrolases (esterases, peptidases, lipases, glycosidas
- Graffner-Nordberg, Malin,Sjoedin, Karin,Tunek, Anders,Hallberg, Anders
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p. 591 - 601
(2007/10/03)
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- Structure-based design and synthesis of lipophilic 2,4-diamino-6- substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents
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The synthesis and biological activities of 14 6-substituted 2,4- diaminoquinazolines are reported. These compounds were designed to improve the cell penetration of a previously reported series of 2,4-diamino-6- substituted-pyrido[2,3-d]pyrimidines which h
- Gangjee, Aleem,Vidwans, Anup P.,Vasudevan, Anil,Queener, Sherry F.,Kisliuk, Roy L.,Cody, Vivian,Li, Ruming,Galitsky, Nikolai,Luft, Joe R.,Pangborn, Walter
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p. 3426 - 3434
(2007/10/03)
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- Stuctural Studies on Bio-active Compounds. Part 5. Synthesis and Properties of 2,4-Diaminopyrimidine Dihydrofolate Reductase Inhibitors bearing Lipophilic Azido Groups
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A series of 2,4-diamino-5-(azidoaryl)-6-alkylpyrimidines has been prepared.The azide (36) (MZP) can be reduced by thiol reagents to the corresponding amine (28) but reductive deazidation occured when the series of azidophenyl derivatives was heated with hydrazine hydrate.Degradation of azide (36) in a trifluoroacetic acid-trifluoromethanesulphonic acid mixture at 0 deg C affords a means of introducing the bulky trifluoromethylsulphonyloxy substituent into the hindered ortho-position of the 5-aryl substituent.The products formed from thermolysis and photolysis of the azide (36) and the planar analogue 2,4-diamino-6-azidoquinazoline (70) derive from the triplet nitrene reactive intermediates. The azido compounds are potent inhibitors of rat liver dihydrofolate reductase although not as active as metoprin.The azide (36), as its ethanesulphonic acid salt, was selected for clinical trial on the basis of its ease of synthesis and suitable biological and pharmaceutical properties, and has a shorter biological half-life than compounds of comparable hydrophobicity.
- Bliss, Edward A.,Griffin, Roger J.,Stevens, Malcolm F. G.
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p. 2217 - 2228
(2007/10/02)
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