Efficient synthesis and structure-activity relationship of honokiol, a neurotrophic biphenyl-type neolignan

Honokiol, a biphenyl-type neolignan, which shows the remarkable neurotrophic effect in primary cultured rat cortical neurons, has been effectively synthesized in 21% yield over 14 steps starting from 5-bromosalicylic acid and p-hydroxybenzoic acid by utilizing Pd-catalyzed Suzuki-Miyaura coupling reaction as a key step. Additionally, the structure-activity relationship between neurite outgrowth-promoting activity and its O-methylated and/or its hydrogenated analogues was examined in the primary cultures of fetal rat cortical neurons, suggesting that 5-allyl and 4'-hydroxyl groups are essential for affecting the neurotrophic activity of honokiol.     

Anti-proliferative activity and structure-activity relationship of honokiol derivatives

As a known natural product with anti-tumor activity, honokiol has been widely researched and structural modified. Lots of honokiol derivatives have been found to possess good anti-proliferative activity and showed great potential in cancer therapy, but the SAR (structure-activity relationship) was still confused. Here in, the SAR were comprehensively researched by summary of reported derivatives and synthesis of novel derivatives. Amongst novel derivatives, the promising compounds A6 and A10 exhibited potent and selective anti-proliferative activities against K562 cell line with the IC₅₀ values of 5.04 and 7.08 μM respectively. The SAR was discussed around honokiol and 79 derivatives by the means of CoMFA and theoretical calculation, which provided useful suggestion for further structural optimization of honokiol derivatives.     

Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons

Honokiol, a main biphenyl neolignan of the traditional crude medicine, Magnoliae cortex, was found to show neurotrophic activity on the cultures of rat cortical neurons at concentration from 0.1 to 10 microM. In the cortical neurons cultured in serum-free medium supplemented with B27, honokiol could promote neurite outgrowth. In addition, the survival and growth of neurons were significantly enhanced by adding honokiol to the primary cultures in serum-free medium supplemented with N2. Its neurotrophic activity was comparable to 40 ng mL(-1) of bFGF at concentration of 10 microM.     

Semi-synthesis and anti-proliferative activity evaluation of novel analogues of Honokiol

A series of honokiol analogues were synthesized by modifying the 5- and/or 3′-position(s) of honokiol to assess their anti-tumor effects. Some compounds exerted more potent anti-proliferative activities than those of honokiol on K562 leukemia cells, A549 alveolar basal epithelial cells, SPC-A1 adenocarcinoma cells and A2780 human ovarian carcinoma cells in vitro. Compounds 2b, 3a, and 3c displayed most potent anti-proliferative activities against these tested cell strains and their anti-drug resistance effects were evaluated in vitro on cisplatin-resistant A2780 human ovarian carcinoma cells. The structure–activity relationship was also proposed.     

Synthesis and neurotrophic activity of nonimmunosuppressant cyclosporin A derivatives

In order to exploit cyclophilin as a potential target for neurological drug design, we demonstrate in this presentation that several nonimmunosuppressant analogues of cyclosporin A, modified at the various positions in the 'effector' domain, are equipotent nerve growth agents compared to cyclosporin A. Our results suggest that neurotrophic activity of cyclosporin A and its derivatives resides in the binding domain, and binding to cyclophilin and/or inhibiting rotamase activity may be a necessity for neurotrophic effects of cyclophilin ligands.     

Synthesis, cytotoxicity, and antiviral activities of new neolignans related to honokiol and magnolol

A series of new bisphenol derivatives bearing allylic moieties were synthesized as potential analogs of honokiol and/or magnolol. Certain compounds exhibited specific anti-proliferation activity against SVR cells and moderate anti-HIV-1 activity in primary human lymphocytes. Compound 5h was the most potent compound and its anti-tumor activity was evaluated in vivo.     

Chlorogenic acid and its metabolite m-coumaric acid evoke neurite outgrowth in hippocampal neuronal cells

We evaluated the neurotrophic activity of dietary polyphenols by using primary cultures of fetal rat hippocampal neurons in a serum-free medium. Among the tested compounds, chlorogenic acid and its metabolite, m-coumaric acid, together with catechins and flavanone, were found to promote neuronal differentiation comparable to the phytochemical, honokiol, which has been reported to show potent neurotrophic activity. The present findings may contribute to the development of further neurotrophic studies on dietary polyphenols and their metabolites.     

Okaramine A,a Novel Indole Alkaloid with Insecticidal Activity,from Penicillium simplicissimum AK-40

We evaluated the neurotrophic activity of dietary polyphenols by using primary cultures of fetal rat hippocampal neurons in a serum-free medium. Among the tested compounds, chlorogenic acid and its metabolite, m-coumaric acid, together with catechins and flavanone, were found to promote neuronal differentiation comparable to the phytochemical, honokiol, which has been reported to show potent neurotrophic activity. The present findings may contribute to the development of further neurotrophic studies on dietary polyphenols and their metabolites.     

Arylpyridines,arylpyrimidines and related compounds as potential modulator agents of the VEGF,hTERT and c-Myc oncogenes

Twenty-four derivatives structurally related to honokiol have been synthesized and biologically evaluated. IC₅₀ values were determined towards the HT-29, MCF-7 and HEK-293 cell lines. Some of these derivatives exhibited comparable or lower IC₅₀ values than honokiol towards the HT-29 and MCF-7 cell lines or else higher selectivity indexes than the natural product. Twelve selected derivatives were evaluated for their ability to inhibit the expression of the VEGFA, hTERT and c-Myc genes and also to inhibit the production of total c-Myc protein and the secretion of the VEGF protein. One of the most promising compounds, 3-(2,4-dimethoxyphenyl)pyridine, may be a good candidate for further studies as an anticancer agent as it is able to improve the effect shown by honokiol in downregulating all gene expression and protein production at a safe concentration for non-tumor cells.     

Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups

A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.     

Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents

Longanlactone analogues were synthesized using a route featuring Friedel-Crafts acylation, Sonogashira coupling and 1,3-dipolar cycloaddition reactions. Structure–activity relationships were investigated for neurotrophic activity. Compound 6 was found to have the most potent neurotrophic activity among all the synthesized analogues in Neuro2a cells as evidenced by a battery of in vitro/cell based assays for assessment of neurogenic and potential neurotrophic activity including neurite outgrowth assay and real time PCR for popular markers of augmented neurotrophic activity. Compound 6 might serve as a template for further development of highly effective neurotrophic molecules.     

An expedient synthesis of honokiol and its analogues as potential neuropreventive agents

An efficient synthesis of honokiol with Suzuki-Miyaura cross coupling obtained an overall yield of 45%. The proposed approach successfully synthesized several structurally similar alkyl, alkenyl and alkynyl analogues, seven of which showed potential neuropreventive activity against MPP(+)-induced and CHP/TBHP oxidative stress induced neuroblastoma cell death.     

Synthesis and Cytotoxic Activity of Novel 5-Substituted-1-(β-L-Arabinofuranosyl) Pyrimidine Nucleosides

A series of new 5-halogeno-1-(ß-L-arabinofuranosyl)uracils and their cytosine analogues were synthesized by halogenation of ara-L-uridine and ara-L-cytidine, respectively. The 5-(2-thienyl) and 5-halogenothienyl derivatives of both series were also prepared in excellent yields by Stille coupling followed by halogenation. All of these syntheses were based on benzoyl-protected derivatives. In vitro cytotoxicity experiments carried out using L1210 mouse leukemia cells showed that 5-(2-thienyl)-ara-L-uridine was the most potent compound of the new compounds; the majority of the analogues were not effective up to 200 μM concentrations.     

Synthesis and in vitro antitumor evaluation of honokiol derivatives

Honokiol is a natural bioactive neolignan and has been widely researched and structural modified as an anticancer agent. In this paper, 18 honokiol derivatives were synthesized and investigated for their antitumor activity. Among these, the promising compound 5a exhibited much higher anti-proliferative activity with IC₅₀ value of 10.41 μM. Transwell assays showed that 5a could significantly inhibit the invasion and migration of I-10 cells at 2.5 μM, which was further confirmed by the western blotting experiments with down-regulation of the HIF-1α and its associated downstream proteins MMP-2 and MMP-9. Overall, these results provided useful suggestion for further structural optimization of honokiol derivatives.     

Inhibition of Herpes Simplex Virus-1 Replication by Natural Compound Honokiol

Honokiol is a pleiotropic natural compound isolated from Magnolia and has multiple biological and clinically relevant effects, including anticancer and antimicrobial function. However, the antiviral activity of honokiol has not yet been well studied. Here we showed that honokiol had no effect on herpes simplex virus-1(HSV-1) entry, but inhibited HSV-1 viral DNA replication, gene expression and the production of new progeny viruses. The combination of honokiol and clinical drug acyclovir augmented inhibition of HSV-1 infection. Our results illustrate that honokiol could be a potential new candidate for clinical consideration in the treatment of HSV-1 infection alone or combination with other therapeutics.     

和厚朴酚对嗜水气单胞菌气溶素表达的抑制作用

为了研究不同浓度和厚朴酚对嗜水气单胞菌(Aeromonas hydrophila)致病力的影响,筛选抗嗜水气单胞菌感染的天然化合物,通过溶血试验、免疫印记试验、荧光定量PCR试验和动物试验进行了研究。结果发现,和厚朴酚能在亚抑菌浓度下降低嗜水气单胞菌培养物上清中的溶血活性;蛋白免疫印迹试验发现和厚朴酚能降低嗜水气单胞菌气溶素的分泌;荧光定量PCR试验进一步表明和厚朴酚与嗜水气单胞菌共培养后降低了气溶素编码基因aerA的转录而降低气溶素的分泌。此外,通过动物试验发现和厚朴酚治疗能显著提高斑点叉尾鮰(Ictalurus punctatus)嗜水气单胞菌感染模型的存活率。以上研究表明,和厚朴酚能通过降低气溶素编码基因aerA的转录而降低嗜水气单胞菌的致病力,和厚朴酚是一种潜在的新型抗嗜水气单胞菌感染的先导化合物。     

Semisynthesis and insecticidal bioactivities of benzoxazole and benzoxazolone derivatives of honokiol,a naturally occurring neolignan derived from Magnolia officinalis

Honokiol, a natural bioactive neolignan isolated from the bark and leaf of Magnolia officinalis and Magnolia obovata, exhibits many important biological properties. In continuation of our interest in discovery of the agrochemicals derived from the natural sources, thirty-seven new 8/8′-alkylthiol-benzoxazole and N-alkyl/sulfonyl-benzoxazolone derivatives of honokiol were prepared and their insecticidal activities were evaluated against the larvae of Mythimna separata Walker and Plutella xylostella Linnaeus. The results showed that eleven derivatives exhibited potent insecticidal activity against M. separata when compared with the positive control. Particularly, compound 5h displayed the most promising insecticidal activity against M. separata with the final mortality rate (FMR) of 58.6%. Meanwhile, compounds 7n (FMR = 65.3%), 7p (FMR = 61.5%), and 8c (FMR = 65.3%) demonstrated a greater insecticidal activity against P. xylostella than toosendanin, a well-known botanical insecticide. Additionally, the preliminary structure-activity relationships (SARs) were also discussed. This study indicates that these honokiol derivatives could be used as leads for the further derivation and development of the potential pesticide candidates for crop protection.     

Design,Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.     

Synthesis of imidazole-containing analogues of farnesyl pyrophosphate and evaluation of their biological activity on protein farnesyltransferase

With the aim of creating new bisubstrate inhibitors of protein farnesyltransferase (FTase), new carboxylic farnesyl pyrophosphate analogues have been designed and synthesized. The original structures are built around three elements: a prenyl moiety, a 1,4-diacid motif and an imidazole ring. All the compounds were evaluated for their ability to inhibit FTase and compared with the corresponding derivatives lacking the imidazole ring, synthesized for that purpose. These new compounds are not bisubstrate inhibitors probably because the imidazole ring is not in the right position to interact with the zinc atom. However these derivatives display FPP competitive inhibition with a good activity in the carboxylic farnesyl pyrophosphate analogues series.     

Novel cofactor derivatives and cofactor-based models

In 1997 and the first half of 1998, numerous publications appeared reporting studies of cofactors and their analogues in classical model systems and in enzyme-catalyzed reactions directed at understanding the enzymatic reactions of their natural cofactors. Model systems based on flavins have provided new insights into enzymatic modulation of the flavin reduction potential, and enzymatic reactions of coenzyme A analogues and derivatives have been employed in several studies of coenzyme A utilizing enzymes. Coenzyme B₁₂ analogues have been utilized as alternate cofactors for B₁₂-utilizing enzymes, while pyrroloquinoline quinone esters and analogues have been employed in model studies of the reactions of quinoprotein-catalyzed reactions.