- Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
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Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
- Linciano, Pasquale,Benedetti, Rosaria,Pinzi, Luca,Russo, Fabiana,Chianese, Ugo,Sorbi, Claudia,Altucci, Lucia,Rastelli, Giulio,Brasili, Livio,Franchini, Silvia
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- Method for synthesizing doxazosin
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The invention discloses a method for synthesizing doxazosin and belongs to the technical field of chemical synthesis. According to the method, the doxazosin is synthesized by adopting a synthesis route, represented by formulae shown in the description, different from the conventional technologies, and thus a novel synthesis route is provided for preparing the doxazosin; and the method has the advantages of moderate conditions, simple and convenient steps and high yield, and the doxazosin can be obtained simply and efficiently.
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- Ultrasound-assisted synthesis and biological evaluation of 1,4-benzodioxane-2-carboxyl-amino acids and Peptides
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A series of peptides containing 1,4-benzodioxane nucleus were attempted to synthesize by conventional as well as green techniques like microwave-assisted and sonication, using dicyclohexylcarbodiimide (DCC) as a coupling reagent and triethylamine as a bas
- Malipeddi, Himaja,Gowda, Visruth,Das, Moonjit
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p. 113 - 118
(2019/01/16)
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- Synthesis and biological evaluation of a series of benzoxazole/ benzothiazole-containing 2,3-dihydrobenzo[b][1,4]dioxine derivatives as potential antidepressants
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A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a-5d and 8a-8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki = 17 nM) and 5-HT2A (Ki = 0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice.
- Wang, Songlin,Chen, Yin,Zhao, Song,Xu, Xiangqing,Liu, Xin,Liu, Bi-Feng,Zhang, Guisen
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supporting information
p. 1766 - 1770
(2014/04/17)
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- Chemoenzymatic synthesis of piperoxan, prosympal, dibozane, and doxazosin
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The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (±)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee ～99%, E = 535) at 258 mmol (50 g/L) substrate concentration.
- Rouf, Abdul,Gupta, Pankaj,Aga, Mushtaq A.,Kumar, Brijesh,Chaubey, Asha,Parshad, Rajinder,Taneja, Subhash C.
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p. 1615 - 1623
(2013/02/22)
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- Synthesis and biological activity of novel carbacyclins having bicyclic substituents on the ω-chain
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A number of carbacyclins having bicyclic substituents on the ω-chain have been synthesized and tested for antiplatelet aggregation activity in vitro (against collagen-induced aggregation of rat platelet), for reduction of systemic blood pressure in vivo (ability to reduce the blood pressure in anesthetized rat by iv injection), and for cytoprotective activity (protection against ethanol-induced rat gastric lesion). The most effective compound for each activity was [3aS-[2E,3aα,4α(3R),5β,6aα]]-5-[hexahydro-5-hydroxy-4-[3-hydroxy-3-(2- indanyl)-1-propynyl]-2(1H)-pentalenylidene]pentanoic acid (compound 11a), while some 1,4-benzodioxan analogues had selectivity for organ-protective activity, and indan analogues showed selectivity in their antiaggregation activity.
- Tomiyama,Wakabayashi,Yokota
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p. 1988 - 1996
(2007/10/02)
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- Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines
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Compounds having the formula STR1 and pharmaceutically acceptable salts thereof wherein R represents 6,7-di(lower alkoxy) or 6,7,8-tri(lower alkoxy); m is 1 or 2, X is --CHR1 -- or --CH2 CH2 --; each R1 and R0 may be the same or different and is hydrogen or lower alkyl; each of R2 and R3 is hydrogen, lower alkoxy, lower alkyl, halogen, lower alkanoyl, lower alkoxycarbonyl, --CONR4 R5 or --SO2 NR4 R5 wherein each of R4 and R5 is hydrogen or lower alkyl; processes for their preparation; and their use as regulators of the cardiovascular system, and particularly in the treatment of hypertension.
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