Design, synthesis, and evaluation of azepine-based cryptophycin mimetics

Cryptophycins, depsipeptides isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins.     

Design,synthesis and biological evaluation of novel isoniazid hybrids

We herein report the design and synthesis of novel isoniazid derivatives. Isoniazid derived Schiff bases (3 a-d) were subjected to cyclization with acetic anhydride and sulphuric acid to yield the 5′-substituted-3′-acetyl-5-(pyridin-4-yl)-3H-spiro[indole-3, 2-[1′, 3′, 4’]oxadiazol]-2′-yl acetates (4 a-d) and 8′-substituted-3’-(pyridin-4-yl)[1′,3′,4’]oxadiazino [6,5-b]indoles (5 a-d) respectively. The advantages of spectral methods were used for the confirmation of the structure of all the newly synthesized hybrid molecules. Further, these compounds were evaluated for their antibacterial activity against B. Subtilis, S. aureus, E. coli & S. typhi, antifungal activity against C. albicans, C. oxysporum, A. Flavus & A. niger, and antimycobacterial activity against M. tuberculosis. Amongst, the compounds 4b, 4c and 5c showed excellent inhibitory activity against tested microorganisms. Also, the DNA cleavage activity of selected compounds was carried out by the AGE method.     

Design, synthesis and biological evaluation of novel glucokinase activators

A new series of benzamide derivatives as glucokinase activators(GKAs) were designed and synthesized,and their activation for glucokinase were evaluated by the preliminary glucokinase activity assay.The structure-activity relationship(SAR) is discussed. The result shows that compound 12d and 12h have potent activity reference drug RO-28-1675.     

Design,synthesis and biological evaluation of LpxC inhibitors with novel hydrophilic terminus

In order to develop novel LpxC inhibitors with good activities and metabolic stability, two series of compounds with hydrophilic terminus have been synthesized and their in vitro antibacterial activities against Escherichial coli and Pseudomonas aeruginosa were evaluated. Especially, compounds 22b and c exhibited comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 and LPC-011 in liver microsomes (rat andmouse), which indicated the terminal methylsulfone may be a preferred structure in the design of LpxC inhibitors and worthy of further investigations.     

Design,synthesis, and biological evaluation of novel histone deacetylase 6 selective inhibitors

Histone deacetylase 6 (HDAC6) is distinguished from other HDACs by its ability to deacetylate α-tubulin and HSP90, and was reported to be related to a variety of human diseases, such as cancers, neurodegenerative diseases, and immunological disorders. The discovery of novel HDAC6 selective inhibitors is important directions of this research field. In this paper, on the basis of a Bcl-2/HDAC6 dual target inhibitor 7g reported by us previously, a novel type of HDAC6 inhibitors was obtained by removing the binding capability to Bcl-2 protein and the subsequent systematical optimization. Among them, compounds Ⅵ-9, Ⅵ-10 and Ⅵ-11 (IC₅₀ = 3.2 ～ 3.9 nM, SI = 20.6 ～ 38.7) showed the best inhibitory activities against and excellent selectivity to HDAC6. These compounds displayed growth inhibitory selectivity to human multiple myeloma cell line over normal cell line, which indicated potential lower toxicity to normal cells and tissues.     

Design,synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents

A series of 3-substituted quinazolinones, 2-substituted quinoxalines and 2-substituted benzopyrans were synthesized and evaluated for their antifungal activity in vitro. The new compounds revealed excellent in vitro antifungal activity with broad spectrum. The structure-activity relationships (SARs) of the derivatives were analyzed. Compound 9A2 exhibits better antifungal activity against 5 tested fungi in vitro than fluconazole, especially against Trichophyton rubrum and Microsporum gypseum. This study provides a series of novel lead compounds for the development of non-azole antifungal agents.     

Enantioselective organocatalytic synthesis of fluorinated molecules

The enantioselective synthesis of fluorinated molecules has drawn much attention within the chemical community due to its unique stereoelectronic properties. The main aim of this review is to cover the most important organocatalytic enantioselective methodologies to obtain them. The review is divided into three parts: first, the direct introduction of a fluorine atom studied in the early 2000s. Second, the later use of Michael reactions to introduce fluorine-containing synthons. Finally, the simultaneously-developed trifluoromethylation reactions, giving the catalysts, mechanisms and reagents that have been used.     

Design,synthesis and biological evaluation of novel dicarbonylalkyl piperazine derivatives as neuroprotective agents

In the search of novel neuroprotective agents with higher potency than our previously identified antiischemic stroke drug candidate 1, a series of novel dicarbonyl piperazine derivatives were synthesized and evaluated on their neuroprotective activity via oxygen–glucose deprivation test in the neuron-like PC12 cells, hypoxia tolerance model in mice and focal cerebral ischemia model in rats. The result obtained indicated that compounds 7f, 7k and 7o, exhibited neuroprotective activity. Particularly,compound 7o containing 2,5-dimethylpiperazin moiety, showed prolonged life time of mice and reduced cerebral infarction of rats, which provided a potential candidate for the development of neuroprotective agents.     

Design,synthesis, molecular docking,and biological evaluation of novel selenium containing lumefantrine analogues

A new series of 1-(9-benzylidene-2,7-dichloro-9H-fluoren-4-yl)-2-(methylselanyl)ethanol was synthesized by a simple Knoevenagel condensation of 1-(2,7-dichloro-9H-fluoren-4-yl)-2-(methylselanyl)ethanol with different substituted aromatic aldehydes in basic media. These synthesized compounds were confirmed on the basis of their elemental analyses, infrared (IR), ¹H NMR, ¹³C NMR, and mass spectral data and screened for the antibacterial and antifungal activity. The preliminary antibacterial and antifungal screening revealed that the compounds 8c (dichloro), 8d (fluoro), 8e (chloro), 8i (methoxy), and 8l (methyl) displayed moderate to good activity. The antibacterial results of these compounds were further supported by in silico molecular docking studies, for the inhibition of Escherichia coli MurB enzyme (PDB code: 2MBR), wherein they showed higher binding energy and good affinity towards the active pocket of the enzyme compared with that of the standard drug Ciprofloxacin. Thus, the plausible mechanism of their antibacterial activity was owed to their inhibitory action of the bacterial MurB enzyme.     

Design and synthesis of cyclic acylguanidines as BACE1 inhibitors

Based on the lead compound 1 reported in literature, a series of novel BACE1 inhibitors were designed and synthesized, among which compound 11 exhibited a 14-fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD.     

Design synthesis and biological evaluation of 3-substituted triazole derivatives

Based on the active site of lanosterol 14α-demethylase of azole antifungal agents,sixteen 1-(1H-1,2,4-triazole-1-yl)- 2-(2,4- difluorophenyl)-3-(N-n-butyl-N-1-substitutedbenzyl-4-methylene-1H-1,2,3-triazole)-2-propanols have been designed,synthesized and evaluated as antifungal agents.Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that some of the compounds exhibited excellent activities with broad spectrum.     

Microwave-assisted synthesis of novel fluorinated 1,2,4-triazole derivatives,and study of their biological activity

Microwave irradiation was used for synthesis of a series of novel fluorinated 1,2,4-triazole derivatives. The molecular structures of the compounds were determined by use of ¹H NMR and FTIR spectroscopy and MS and HRMS. Study of their biological activity showed most of the compounds had good herbicidal activity.     

Design,synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Background

Glycyrrhetinic acid (GA) derivatives had shown not only cytotoxicity but also could trigger apoptosis in various human cancer cell lines. Moreover, cinnamic acid (CA) and its phenolic analogues as potent antitumor agents were employed in the design of anti-tumor drugs. To further improve the anti-tumor activity of GA and CA derivatives, a series of novel compounds were designed and synthesized using GA and CA derivatives fragments.

Results

The result showed that all the novel glycyrrhetinic acid-cinnamoyl (GA–CA) hybrids presented higher antitumor activity on the tumor cell lines of HepG2, HT-29, Hela and lower cytotoxicity on three non-tumor cells lines MDCK, HY926, H9C2 than the parent compounds (IC₅₀ > 50 μM). It was worth noting that 8a had a superior cytotoxicity effect on Hela cells (IC₅₀ = 8.54 μM) than on other cancer cell lines (IC₅₀ > 15 μM). And it also indicated that 8a showed lower cytotoxicity (IC₅₀ > 27 μM) towards MDCK, HY926 and H9C2 cells than cisplatin (DDP, IC₅₀ < 10 μM). Moreover, according to the acute toxicity, it could be indicated that the LD₅₀ of 8a exceeded 3.0 g/kg by oral administration in mice. The further research using Giemsa, H33342 staining, flow cytometric analysis and caspase-3 assay showed that 8a could cause Hela cell damage, nuclei lysis and apoptosis. In addition, the structure–activity relationships of these hybrids were briefly discussed.

Conclusions

Compared with GA, target compounds demonstrated better anti-tumor activity, among which 8a was the most active one. What’s more, structure–activity relationship analysis also revealed that hybrids with trans olefinic bond group show higher antitumor activity than those without olefinic bond, such as 1a > 1b, 6a > 2b, 8a > 3b, 9a > 4b. In addition, it was found that the methoxy substituent might enhance selectivity of GA–CA hybrids towards regular non-cancerous cells MDCK, HY926 and H9C2, such as 4a, 6a, 7a, 8a. However, there might be less relationship between the cytotoxicity and the quantity, position of methoxy moiety. Hence, it is urgent need to synthesize efficient, low toxicity and multi-target anti-tumor compounds based on the structure combination principle.

     

Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids

Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C3'BzN), which are ca. 7.5 A apart, with a short linker (4-6 atoms). 7-TES-14beta-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-beta-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.     

Design,synthesis and biological evaluation of E-ring modified evodiamine derivatives as novel antitumor agents

A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase Ⅰ and Ⅱ was evaluated by the relaxation assay. In vitro antitumor activity results revealed that compound 12 showed good antitumor activity with a broad spectrum. Its binding modes with topoisomerase Ⅰ and Ⅱ were clarified by molecular docking.     

Design,synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.     

Design,synthesis and biological evaluation of novel 3-phenylpropanamide derivatives with acyl hydrazone units

In this study, a series of 3-phenylpropanamide derivatives with acyl hydrazone units were synthesized and characterized by ¹H NMR, ¹³C NMR and HR MS. And the structure of compound III₃₃ was confirmed by X-ray single crystal. The bioassay results showed that, compounds III₈, III₁₇, III₂₂, and III₃₄ showed excellent inhibition on Xanthomonas oryzae pv. pryzae (Xoo) with EC₅₀ values of 7.1, 8.8, 9.5, and 4.7 μg/mL in vitro. The EC₅₀ values of compounds III₁₂, III₁₄ and III₃₃ against Ralstonia solanacearum (Rs) were 7.6, 7.6 and 7.9 μg/mL, respectively, all lower than the values of thiadiazol copper (TC) was 66.8 μg/mL and bismerthiazol (BT) was 72.4 μg/mL. Compounds III₁₂, III₁₄, III₃₃, and III₃₄ exhibited excellent antibacterial activity of more than 80% against Xanthomonas axonopodis pv. citri (Xac) in vitro. Besides, compounds III₈ (51.4%) and III₃₄ (52.1%) were highly effective against Xoo in vivo, outperforming TC (49.5%) and BT (47.8%). Compounds III₈ (29.8%) and III₃₄ (24.6%) were close to TC (41.7%) and BT (47.8%) in terms of protective efficacy against Xoo in vivo. Meanwhile, some of title compounds also displayed inhibitory effects against phytopathogenic fungi. In a word, this study illustrated that the structures combined with phenylpropane amide derivatives of the acyl hydrazone units could be used as potential antibacterial reagents in the future.     

Design, synthesis, and biological evaluation of somatostatin-based radiopeptides

The prototypes for tumor targeting with radiolabeled peptides are derivatives of somatostatin. Usually, they primarily have high affinity for somatostatin receptor subtype 2 (sst2), and they have moderate affinity for sst5. We aimed at developing analogs that recognize different somatostatin receptor subtypes for internal radiotherapy in order to extend the present range of accessible tumors. We synthesized DOTA-octapeptides based on octreotide by replacing Phe3 mainly with unnatural amino acids. The affinity profile was determined by using cell lines transfected with sst1-5. Internalization was determined by using AR42J, HEK-sst3, and HEK-sst5 cell lines, and biodistribution was studied in rat tumor models. Two of the derivatives thus obtained showed an improved binding affinity profile, enhanced internalization into cells expressing sst2 and sst3, respectively, and better tumor:kidney ratios in animals.     

Facile synthesis of wide-bandgap fluorinated graphene semiconductors

The bandgap opening of graphene is extremely important for the expansion of the applications of graphene-based materials into optoelectronics and photonics. Current methods to open the bandgap of graphene have intrinsic drawbacks including small bandgap openings, the use hazardous/harsh chemical oxidations, and the requirement of expensive chemical-vapor deposition technologies. Herein, an eco-friendly, highly effective, low-cost, and highly scalable synthetic approach is reported for synthesizing wide-bandgap fluorinated graphene (F-graphene or or fluorographene) semiconductors under ambient conditions. In this synthesis, ionic liquids are used as the only chemical to exfoliate commercially available fluorinated graphite into single and few-layer F-graphene. Experimental and theoretical results show that the bandgap of F-graphene is largely dependent on the F coverage and configuration, and thereby can be tuned over a very wide range.