- Design and Synthesis of Tetrazole- And Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors
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Itraconazole, a widely used antifungal drug, was found to possess antiangiogenic activity and is currently undergoing multiple clinical trials for the treatment of different types of cancer. However, it suffers from extremely low solubility and strong interactions with many drugs through inhibition of CYP3A4, limiting its potential as a new antiangiogenic and anticancer drug. To address these issues, a series of analogs in which the phenyl group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound 24 has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound 24 inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2. It also induced cholesterol accumulation in the endolysosome and demonstrated binding to the sterol-sensing domain of NPC1 in a simulation study. These results suggested that compound 24 may serve as an attractive candidate for the development of a new generation of antiangiogenic drug.
- Cheng, Zhiqiang,Head, Sarah A.,Li, Ruo-Jing,Li, Yingjun,Liu, Jun O.,Liu, Wukun,Pasunooti, Kalyan Kumar,Peng, Hanjing,Shi, Wei Q.
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p. 1111 - 1117
(2020/07/04)
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- An optical pure itraconazole key intermediate and synthetic method and by the intermediate synthesis of optically pure itraconazole method
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The invention disclsoes an optically pure itraconazole key intermediate and synthetic method thereof, and a method for synthesizing the optically pure itraconazole from the intermediate. The method of the invention uses 1-(2,4-dichlorobenzene)-2-(1-methylene-1,2,4-triazole)-1-ketone for preparing the optically pure itraconazole key intermediate, and the optically pure itraconazole key intermediate is used for the preparation of optically pure itraconazole. The method uses easily available raw materials, not only reduces the production cost, but also obtains the product with high purity; through the control of the optical purity of the key intermediate compound VII, the optical purity of the target product itraconazole can be effectively controlled; therefore, the invention has with industrial value.
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- Prepartion method of itraconazole
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The invention discloses a preparation method of itraconazole. Raceme-glycidol which is cheap and easy to obtain is adopted as raw materials, hydroxyls at the two ends are protected by trityl and benzyl and then esterified by 2,4-dichlorobenzene formyl chloride, then, a silylation Grignard addition reaction and a beta-silicyl alcohol elimination reaction are adopted for reducing carbonyl into carbon-carbon double bonds, iodine is adopted for performing an olefin addition reaction and a stereoselectivity ring-closure reaction, triazole replacement and debenzylation are performed, and tosyl is introduced to obtain a compound 9; the compound and a compound 10 are subjected to a condensastion reaction to obtain itraconazole; the overall synthesis process is small in pollution, easy to process, few in by-product, high in reaction selectivity and purity, environmentally friendly, low in production cost and suitable for industrial production; the defects that in the prior art, the selectivity is poor, multiple by-products are produced, the yield is low, and expensive catalysts and reagents with large environmental pollution are avoided are avoided.
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Paragraph 0068; 0069
(2017/04/29)
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- Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
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Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
- Pace, Jennifer R.,Deberardinis, Albert M.,Sail, Vibhavari,Tacheva-Grigorova, Silvia K.,Chan, Kelly A.,Tran, Raymond,Raccuia, Daniel S.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
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p. 3635 - 3649
(2016/05/24)
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- Asymmetric synthesis and effect of absolute stereochemistry of YCZ-2013, a brassinosteroid biosynthesis inhibitor
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The four stereoisomers of 2RS,4RS-1-[[2-(2,4-dichlorophenyl)-4-(2-(2- propenyloxy)phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (YCZ-2013), a novel brassinosteroid biosynthesis inhibitor, were prepared. The diastereomers of 2RS,4R-5 and 2RS,4S-5 were prepared by using the corresponding optically pure R and S toluene-4-sulfonic acid 2,3-dihydroxypropyl ester (R-4,S-4). The enatiomerically and diastereomerically pure acetonide (5) was obtained by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and 2R,4S-YCZ-2013 exhibited potent inhibitory activity with IC50 values of approximately 24 ± 3 and 24 ± 2 nM, respectively. The IC50 values of the trans isomers of 2S,4S-YCZ-2013 and 2R,4R-YCZ-2013 are approximately 1510 ± 50 and 3900 ± 332 nM, respectively. Co-application of brassinolide (10 nM), the most potent BR, and GA3 (1 μM) to Arabidopsis seedlings grown in the dark with 2R,4S-YCZ-2013 and 2S,4R-YCZ-2013 revealed that brassinolide recovered the induced dwarfism of Arabidopsis seedlings, whereas GA3 showed no effect.
- Oh, Keimei,Yamada, Kazuhiro,Yoshizawa, Yuko
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p. 6915 - 6919
(2014/01/06)
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- Impact of absolute stereochemistry on the antiangiogenic and antifungal activities of itraconazole
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Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a?h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the antiangiogenic and antifungal activities of itraconazole.
- Shi, Wei,Nacev, Benjamin A.,Bhat, Shridhar,Liu, Jun O.
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scheme or table
p. 155 - 159
(2010/10/19)
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- CHIRALLY PURE ISOMERS OF ITRACONAZOLE AND INHIBITORS OF LANOSTEROL 14A- DEMETHYLASE FOR USE AS ANGIOGENESIS INHIBITORS
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Described herein are methods of inhibiting angiogenesis, and treating or preventing a disease or disorder (or symptoms thereof) associated with angiogenesis, wherein an anti-angiogenesis compound is administered to a subject.
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- Total synthesis of (2R,4S,2′S,3′R)-hydroxyitraconazole: Implementations of a recycle protocol and a mild and safe phase-transfer reagent for preparation of the key chiral units
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A convergent total synthesis of enantiomerically-pure (2R,4S,2′S, 3′R)-hydroxyitraconazole 1b is described. The left dioxolane portion of the molecule was prepared in good yield by the conversion of (S)-10 to the corresponding enantiomerically and diastereomerically-pure acetonide (2R,4R)-3 by a recycle protocol involving diastereoselective crystallization of the tosylate salt, followed by re-equilibration of the mother liquor and crystallization. The right-hand triazolone moeity (2S,3R)-4 was generated by alkyaltion of triazolone 6 with enantiomerically pure cyclic sulfate (4R,5R)-7 under mild and essentially non-hazardous reaction conditions (TDA-1, K 2CO3, acetonitrile).
- Tanoury, Gerald J.,Hett, Robert,Wilkinson, H. Scott,Wald, Stephen A.,Senanayake, Chris H.
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p. 3487 - 3493
(2007/10/03)
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- Synthesis, antifungal activity and structure-activity relationships of 2-(alkyl or aryl)-2-(alkyl or polyazol-1-ylmethyl)-4-(polyazol-1-ylmethyl)- 1,3-dioxolanes
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A series of 2-(alkyl or aryl)-2-(alkyl or polyazol-1-ylmethyl)-4-(polyazol-1-ylmethyl)-1,3-dioxolanes Ia-u was synthesized and tested in vitro against pathogenic fungi in man, animals and plants: Candida albicans, Aspergillus flavus and Fusarium solani. Compounds Iq-t with two polyazol groups have an in vitro activity against these fungi with MIC (minimum inhibitory concentration) value of 5 μg mL-1.
- Baji,Kimny, Tan,Gasquez,Flammang,Compagnon,Delcourt,Mathieu,Viossat,Morgant,Nguyen-Huy
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p. 637 - 650
(2007/10/03)
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- Synthesis and antifungal activity of novel (1-aryl-2-heterocyclyl)ethylideneaminooxymethyl-substituted dioxolanes
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A novel series of (1-aryl-2-heterocyclyl)ethylideneaminooxymethyl-substituted dioxolanes IIIa-n were synthesized by condensation of substituted 1,3-dioxolan-4-ylmethyl p-toluenesulfonates 4 with 1-(hydroxyimino)-1-aryl-2-heterocyclylethanes 5.Compounds IIIa-n were found to have effective in vitro antifungal activity when evaluated against the pathogenic fungi Candida albicans, Aspergillus flavus and Fusarium solani with MIC (minimum inhibitory concentration values of 10 μg*ml-1 for IIIa-l and 5 μg*ml-1 for IIIm,n. antifungal activity / 1,3-dioxolane / ethylideneaminooxy / imidazole / 1,2,4-triazole
- Baji, H.,Flammang, M.,Kimny, T.,Gasquez, F.,Compagnon, P. L.,Delcourt, A.
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p. 617 - 626
(2007/10/02)
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