Synthesis and SAR studies of marine natural products ma’edamines A,B and their analogues

The synthesis of several analogues of ma’edamines A and B are reported. The synthesized compounds were tested on hormone receptor positive and HER2 positive breast cancer cell lines, by MTT assay. MED-114, 115, 117, 119, 120, 124, 128 and 131 were found to be equally active as Lapatinib on HER2 +ve cell line SKBR3.     

The synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranoses, a novel class of α-glucosidase inhibitors

The asymmetric synthesis of 1-C-alkyl-l-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC₅₀ values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC₅₀ = 0.032 μM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.     

Chemical synthesis and biological evaluation of ω-hydroxy polyunsaturated fatty acids

ω-Hydroxy polyunsaturated fatty acids (PUFAs), natural metabolites from arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were prepared via convergent synthesis approach using two key steps: Cu-mediated CC bond formation to construct methylene skipped poly-ynes and a partial alkyne hydrogenation where the presence of excess 2-methyl-2-butene as an additive that is proven to be critical for the success of partial reduction of the poly-ynes to the corresponding cis-alkenes without over-hydrogenation. The potential biological function of ω-hydroxy PUFAs in pain was evaluated in naive rats. Following intraplantar injection, 20-hydroxyeicosatetraenoic acid (20-HETE, ω-hydroxy ARA) generated an acute decrease in paw withdrawal thresholds in a mechanical nociceptive assay indicating pain, but no change was observed from rats which received either 20-hydroxyeicosapentaenoic acid (20-HEPE, ω-hydroxy EPA) or 22-hydroxydocosahexaenoic acid (22-HDoHE, ω-hydroxy DHA). We also found that both 20-HEPE and 22-HDoHE are more potent than 20-HETE to activate murine transient receptor potential vanilloid receptor1 (mTRPV1).     

The first stereoselective total synthesis of (Z)-cryptomoscatone D2, a natural G₂ checkpoint inhibitor

The first stereoselective synthesis of (Z)-cryptomoscatone D2, a naturally occurring G(2) checkpoint inhibitor, was accomplished using propane-1,3-diol as the starting material. The Maruoka asymmetric allylation, ring closing metathesis and the hydrogenation of the triple bond employing Lindlar's catalyst were involved as the key steps.     

Design,synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer’s disease

With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer’s disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer’s disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC₅₀ values about 44.67–169.80 nM (donepezil IC₅₀ 50.12 nM). Notably, compound 12 presented potent activities against PDE5A with IC₅₀ values about 50 μM (sildenafil IC₅₀ 12.59 μM), and some of these compounds showed low cell toxicity to A549 cells in vitro.     

Design,synthesis and biological evaluation of a bivalent μ opiate and adenosine A1 receptor antagonist

The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A₁ adenosine and μ opiate receptors with a K_i of 0.8 ± 0.05 and 0.7 ± 0.03 μM, respectively. This hybrid molecule increases cAMP production in cells that over express the μ receptor as well as those over expressing the A₁ adenosine receptor and reverses the antalgic effects of μ and A₁ adenosine receptor agonists in animals.     

Design,synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase

To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC₅₀ = 0.567 μM; AChE: IC₅₀ = 1.83 μM), and also showed excellent inhibitory effects on Aβ production of APP transfected HEK293 cells (IC₅₀ = 98.7 nM) and mild protective effect against hydrogen peroxide (H₂O₂)-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Aβ_1–40 production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.     

The synthesis and biologic evaluation of anti-platelet and cytotoxic β-nitrostyrenes

Our previous studies demonstrated that two cytotoxic β-nitrostyrene derivatives, 3,4-methylenedioxy-β-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxy-β-nitrostyrene (BMNS) exhibit potent anti-platelet activities. In this study, a series of β-nitrostyrenes were synthesized and subjected to anti-platelet aggregation assay and cytotoxicity assay. The mono- and di-substitutions on the B ring of BMNS tended to increase the anti-platelet activity and decrease the cytotoxic activity. Of these, compounds 19 and 24 exhibited the most potent inhibitory effects on thrombin- and collagen-induced platelet aggregation (IC₅₀ ? 0.7 μM) without significant cytotoxicity on a human cancer cell line (up to 20 μM). Further studies indicated that compounds 19 and 24 inhibited platelet aggregation via prevention of glycoprotein IIb/IIIa activation. The potent and novel effects of BMNS derivatives make them attractive candidates for the development of new anti-platelet agents.     

The synthesis and evaluation of indolylureas as PKCα inhibitors

PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.     

Design,synthesis and biological evaluation of benzylisoquinoline derivatives as multifunctional agents against Alzheimer’s disease

A novel series of benzylisoquinoline derivatives were designed, synthesized, and evaluated as multifunctional agents against Alzheimer’s disease (AD). The screening results showed that most of the compounds significantly inhibited cholinesterases (ChEs), human cholinesterases (h-ChEs) and self-induced β-amyloid (Aβ) aggregation. In particular, compound 9k showed the strongest acetylcholinesterase (AChE) inhibitory activity, being 1000-fold and 3-fold more potent than its precursor benzylisoquinoline (10) and the positive control galanthamine, respectively. In addition, 9k was a moderately potent inhibitor for h-ChEs. Compared with precursor benzylisoquinoline (36.0% at 20 μМ), 9k (78.4% at 20 μМ) could further inhibit Aβ aggregation. Moreover, 9k showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Therefore, compound 9k might be a promising lead compound for AD treatment.     

Design,synthesis and biological evaluation of metronidazole–thiazole derivatives as antibacterial inhibitors

A series of metronidazole–thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, ¹H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5e exhibited the most potent inhibitory activity against E. coli FabH with IC₅₀ of 4.9 μM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5a, 5b, 5d, 5e, 5g and 5i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.     

Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13nM) and cellular (IC(50)=21nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.     

Design,synthesis and biological evaluation of estradiol–chlorambucil hybrids as anticancer agents

A series of estradiol–chlorambucil hybrids was synthesized as anticancer drugs for site-directed chemotherapy of breast cancer. The novel compounds were synthesized in good yields through efficient modifications of estrone at position 16α of the steroid nucleus. The newly synthesized compounds were evaluated for their anticancer efficacy in different hormone-dependent and hormone-independent breast cancer cell lines. The novel hybrids showed significant in vitro anticancer activity when compared to chlorambucil. Structure–activity relationship (SAR) reveals the influence of the length of the spacer chain between carrier and drug molecule.     

Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors

Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.     

Hybrid α-bromoacryloylamido chalcones. Design,synthesis and biological evaluation

Research into the anti-tumor properties of chalcones has received significant attention over the last few years Two novel large series of α-bromoacryloylamido chalcones 1a–m and 2a–k containing a pair of Michael acceptors in their structures, corresponding to the α-bromoacryloyl moiety and the α,β-unsaturated ketone system of the chalcone framework, were synthesized and evaluated for antiproliferative activity against five cancer cell lines. Such hybrid derivatives demonstrated significantly increased anti-tumor activity compared with the corresponding amino chalcones. The most promising lead molecules were 1k, 1m and 2j, which had the highest activity toward the five cell lines. Flow cytometry with K562 cells showed that the most active compounds resulted in a large proportion of the cells entering in the apoptotic sub-G0–G1 peak. Moreover, compound 1k induced apoptosis through the mitochondrial pathway and activated caspase-3.     

Total synthesis and biological evaluation of novel C2–C6 region analogues of dictyostatin

By exploiting a Still–Gennari HWE coupling with a common C11–C26 aldehyde, a series of C2–C6 modified analogues of the microtubule-stabilising marine natural product dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the (P-glycoprotein efflux-mediated) Taxol-resistant NCI/ADR cell line. Removal of the C6 methyl substituent in dictyostatin was found to be well tolerated and led to the retention of antiproliferative activity in the low nanomolar range (IC₅₀ = 43 nM in the NCI/ADR cell line), while partial and full saturation of the (2Z, 4E)-dienoate region led to a progressive reduction in biological potency. The lactone ring size was found to be critical, as C21 to C19 translactonisation to afford 20-membered isodictyostatin analogues led to a significant loss of cytotoxicity. In a series of incubatory experiments performed on the PANC-1 cell line, all three of the 22-membered macrolide analogues acted in an analogous fashion to dictyostatin, through a mechanism of microtubule stabilization, causing both an accumulation of cells at the G2/M phase and formation of characteristic dense intracellular microtubule bundles.     

The first protein ever synthesized in vitro—a personal reminiscence of the total synthesis of crystalline insulin

<正>The total synthesis of crystalline bovine insulin started in 1958 was fully accomplished in 1965. This formidable task was a collaboration of the Institute of Biochemistry in Shanghai,     

Design,synthesis and biological evaluation of novel coumarin thiazole derivatives as α-glucosidase inhibitors

A new series of coumarin thiazole derivatives 7a-7t were synthesized, characterized by ¹H NMR, ¹³C NMR and element analysis, evaluated for their α-glucosidase inhibitory activity. The majority of the screened compounds displayed potent inhibitory activities with IC₅₀ values in the range of 6.24 ± 0.07–81.69 ± 0.39 μM, when compared to the standard acarbose (IC₅₀ = 43.26 ± 0.19 μM). Structure–activity relationship (SAR) studies suggest that the pattern of substitution in the phenyl ring is closely related to the biological activity of this class of compounds. Among all the tested molecules, compound 7e (IC₅₀ = 6.24 ± 0.07 μM) was found to be the most active compound in the library of coumarin thiazole derivatives. Enzyme kinetic studies showed that compound 7e is a non-competitive inhibitor with a K_i of 6.86 μM. Furthermore, the binding interactions of compound 7e with the active site of α-glucosidase were confirmed through molecular docking. This study has identified a new class of potent α-glucosidase inhibitors for further investigation.     

Improved synthesis and biological evaluation of chelator-modified α-MSH analogs prepared by copper-free click chemistry

Radionuclide chelators (DOTA, NOTA) functionalized with a monofluorocyclooctyne group were prepared. These materials reacted rapidly and in high yield with a fully deprotected azide-modified peptide via Cu-free click chemistry under mild reaction conditions (aqueous solution, room temperature). The resulting bioconjugates bind with high affinity and specificity to their cell-surface receptor targets in vitro and appear stable to degradation in mouse serum over 3h of incubation at 37°C.     

Design,synthesis, quantum chemical studies and biological activity evaluation of pyrazole–benzimidazole derivatives as potent Aurora A/B kinase inhibitors

Novel pyrazole–benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence.