- Method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane
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The invention discloses a method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane. The method comprises the following steps: (1) preparing an intermediate I by using N-Boc-trans-4-hydroxy-L-proline methyl ester as a raw material; (2) preparing an intermediate II by reacting the intermediate I with an organic base and a sulfonylating reagent; (3) preparing an intermediate III from the intermediate II and benzylamine; and (4) finally preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane by debenzylating the intermediate III. The method provided by the invention simplifies reaction steps, reduces raw material cost and time cost, has high product yield, tends to purify and amplify production, and can reduce waste discharge.
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- Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate-nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines
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The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical cancer cell lines superior to Cisplatin and Paclitaxel with IC50 values 0.99 ± 0.007, 2.36 ± 0.016 and 0.73 ± 0.002 μM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the cancer cell proliferation by inducing apoptosis through caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki cancer cells. At the predetermined IC50 values on cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11.
- Laskar, Sujay,Sánchez-Sánchez, Luis,Flores, Sebastián M.,López-Mu?oz, Hugo,Escobar-Sánchez, María L.,López-Ortiz, Manuel,Hernández-Rodríguez, Marcos,Regla, Ignacio
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p. 621 - 635
(2018/02/09)
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- Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis
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Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.
- Laskar, Sujay,Sánchez-Sánchez, Luis,López-Ortiz, Manuel,López-Mu?oz, Hugo,Escobar-Sánchez, María L.,Sánchez, Arturo T.,Regla, Ignacio
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p. 1129 - 1135
(2017/09/18)
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- Preparation method for (1S,4S)-2,5-diazabicyclo[2.2.1]heptane or (1S,4S)-2,5-diazabicyclo [2.2.1]octane derivative
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The invention discloses a preparation method for a (1S,4S)-2,5-diazabicyclo[2.2.1]heptane or (1S,4S)-2,5-diazabicyclo [2.2.1]octane derivative. The method comprises the following steps: subjecting a hydroxyl group of five-component or six-component N-heterocycle to sulfonylation by using a sulfonylation reagent; then subjecting sulfonate to a substitution reaction of SN2 by using an azide; simultaneously reducing an azido group and an ester group by using a reduction reaction; and finally, carrying out ring closure so as to obtain the derivative. The synthesis route of the preparation method has higher selectivity compared with the prior art; reaction steps are reduced; cost for raw materials and time cost are saved; product yield is substantially higher than product yield in the prior art; and the preparation method can easily realize purification and enlarged production and reduce discharging of waste.
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- A practical synthesis of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane
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The rigid piperazine homologue 2,5-diazabicyclo[2.2.1]heptane (DBH) finds extensive application in medicinal chemistry and pharmaceutical research, but access to this scaffold is non-trivial. This letter details a concise synthetic sequence that gives ready access to DBH on gram scale. The route features a Staudinger reduction of an azide to facilitate a transannular cyclisation.
- Beinat, Corinne,Banister, Samuel D.,McErlean, Christopher S.P.,Kassiou, Michael
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supporting information
p. 5345 - 5347
(2013/09/12)
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- The synthesis and biological evaluation of a novel series of C7 non-basic substituted fluoroquinolones as antibacterial agents
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A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46-85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates. Crown Copyright
- Huang, Xiaoguang,Chen, Dongliang,Wu, Ning,Zhang, Aiqin,Jia, Zhenhua,Li, Xingshu
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scheme or table
p. 4130 - 4133
(2010/04/26)
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- Design, Synthesis, and Properties of (4S)-7-(4-Amino-2-substituted-pyrrolidin-1-yl)quinolone-3-carboxylic Acids
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The quinolinecarboxylic acids constitute a class of extremely potent and orally active broad-spectrum antibacterial agents.These compounds have been shown to inhibit DNA gyrase, a key enzyme in bacterial DNA replication.The 7-(3-aminopyrrolidinyl)quinolone A-60969 (1) is a particularly potent member of this class and is currently undergoing clinical evaluation.We have studied a series of enantiomerically homogeneous (4S)-7-(4-amino-2-substituted-pyrrolidinyl)quinolones in an effort to utilize the 2-position of the pyrrolidine moiety to improve upon the solubility and pharmacokinetic properties of this class of compounds while still maintaining potent antibacterial activity.We have found that the absolute stereochemistry at the 2-position of the pyrrolydine ring is critical to the maintenance of such activity.In this paper, we report the full details of the asymmetric synthesis and the in vitro and in vivo structure-activity relationships of this series of compounds as well as the physiochemical properties, such as water solubility and log P, associated with the structural modifications.We also discuss the pharmacokinetic properties of several of these compounds in mice and the pharmacokinetics of 59, which has the best overall properties of agents in this study, in dog.
- Rosen, Terry,Chu, Daniel T. W.,Lico, Isabella M.,Fernandes, Prabhavathi B.,Marsh, Kennan,et al.
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p. 1598 - 1611
(2007/10/02)
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