1.Crystal engineering approach to produce complex of azelnidipine with maleic acid
Weiguang Lian, Yulong Lin, Min Wang, Caiqin Yang and Jing Wang*. CrystEngComm, 2013, 15, 3885–3891
The PXRD patterns of the azelnidipine–maleic acid system are shown in Fig. 2. When azelnidipine is coground with maleic acid at a molar ratio of 1 : 1 and 1 : 2 for 15 min and 60 min, the obvious halo patterns are observed (Fig. 2e–h), indicating the amorphous phase of the grinding mixture. This result suggests that the azelnidipine : maleic acid ratio of 1 : 1 and 1 : 2 might not be a suitable stoichiometry for the complex formation, even if grinding time is considered to be optimized. Whereas, new obvious PXRD peaks at 2 = 6.3o, 12.6o, 14.5o, 15.5o, 20.1o, 21.5o, 22.6o, and 25.5o were observed for the complex at the azelnidipine : maleic acid molar ratio of 2 : 1 (Fig. 2c and d). Peak positions of those new peaks were apparently different from those of the starting components, suggesting that crystalloid azelnidipine–maleic acid complex was formed by solvent-assisted co-grinding and prolonged grinding time did not induce the disorder of solid into the amorphous phase. The final azelnidipine–maleic acid complex stoichiometry was close to 2 : 1 within the detection limit of PXRD.
2. Iron catalysed cross-couplings of azetidines –application to the formal synthesis of a pharmacologically active molecule
Dixit Parmar, Lena Henkel, Josef Dib and Magnus Rueping*. Chem. Commun., 2015, 51, 2111—2113
Small nitrogen-containing heterocycles are highly desirable structural motifs, which when installed within molecules can provide beneficial attributes sought after in both the agrochemical and pharmaceutical industries. Within this family, azetidines are particularly interesting units since they possess a reasonable stability whilst providing strong molecular rigidity. Azetidines can be found both in nature and in numerous practical applications with perhaps the highest-profile azetidine being azelnidipine whichissoldasacalciumchannelblocker. Closely related to this, azetidines possessing aryl substitution at the 3-position are highly sought after compounds and have been found to display an array of pharmacological activities.
3. Binding mechanisms of 1,4-dihydropyridine derivatives to L-type calcium channel Cav1.2 a molecular modeling study
Lei Xu, Dan Li, Li Tao, Yanling Yang, Youyong Li and Tingjun Hou*. Mol. BioSyst., 2016, 12, 379—390
In this study, amlodipine, nifedipine and felodipine, three most popular drugs for the treatment of cardiovascular diseases, and the other three drugs, including nimodipine, azelnidipine and benidipine, with diﬀerent chiral centers and substituents, were chosen as the studied systems. It should be noted that some clinically used DHP derivatives are racemic mixture with chiral centers, but the calcium-channel modulation capability is dependent on the absolute configuration. For example, amlodipine is a racemic mixture containing (R) and (S)-amlodipine isomers in a 1 : 1 ratio, but only (S)-amlodipine has eﬀective therapeutic potency. In order to understand the mechanism of stereoselectivity of enantiomers, the bindings of (R)- and (S)-amlodipines to human Cav1.2 were explored and compared. For the other four DHP derivatives with chiral centers, only the most active isomers were considered. Therefore, in total, seven DHP derivatives were studied here, including (R)-amlodipine, (S)-amlodipine, nifedipine, (S)-nimodipine, (S)-felodipine, (S,S)-azelnidipine and (S,S)-benidipine. First, homology modeling was carried out to construct the 3D model of the central pore region of the a1c subunit of human Cav1.2 based on the crystal structure of the bacterial voltage-gated calcium (Cav) channel. Then, induced fit docking (IFD) was employed to construct the binding structures of the DHP derivatives in complex with Cav1.2. The best complex structure for each DHP derivative predicted by IFD was submitted to 50 ns molecular dynamics (MD) simulations and the binding aﬃnity between each ligand and Cav1.2 was predicted by the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) approach. We expect that the predicted structures could be useful to design potent and selected ligands of Cav1.2.
4. Fucoidan from Undaria pinnatiﬁda prevents vascular dysfunction through PI3K/Akt/ eNOS-dependent mechanisms in the L-NAME-induced hypertensive rat model
Xiaofei Li, Jian Li, Zhike Li, Hong Ding* and Shanye Yin*. Food Funct.,2016, 7,2398–2408
Calcium channel blockers (CCBs) are a widely utilized first-line antihypertensive agent; representative drugs included nifedipine and azelnidipine. As the primary and clinically eﬀective hypertension therapeutic, CCBs have a number of undesirable pharmacokinetic and pharmacodynamics properties, including first-pass metabolism, short half-life and photodegradation. Moreover, adverse reactions occur frequently, such as nifedipine-induced gingival enlargement as found in recent years. To overcome these disadvantages, new therapeutic targets and corresponding interventions have been designed to address these pharmacodynamic properties (with-drawal reaction and adverse reactions). We therefore investigate whether fucoidan from Undaria pinnatifida could influence NO production in vitro by stimulation of eNOS activation and Akt pathway. We further utilized a rat hypertension model of vascular endothelial injury induced by chronic blockade of nitric oxide (NO) to examine the function of fucoidan treatment in vitro.