Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential.

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (Ki = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [35S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 2.59 nM, E(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.

Design, synthesis, fungicidal activities and structure-activity relationship studies of (-)-borneol derivatives containing 2-aryl-thiazole scaffold.

A series of (-)-borneol derivatives containing 2-aryl-thiazole scaffold were designed, synthesized, and characterized by 1H NMR, 13C NMR, and HRMS. The fungicidal activities of these novel compounds against Fusarium oxysporum, Magnaporthe grisea, Botrytis cinerea, and Penicillium digitatum were evaluated. The results indicated that (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(Z)-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)amino)but-2-enoate (6a) displayed potential fungicidal activities with broad spectrum. Especially, 6a exhibited an IC50 value of 48.5 mg/L against P. digitatum, which has higher fungicidal activity than commercial products hymexazol and amicarthiazol. Moreover, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)amino)butanoate (5a) possesses an IC50 value of 24.3 mg/L against B. cinerea, comparable to hymexazol and far superior to amicarthiazol. Furthermore, the superficial structure-activity relationship was discussed, which might be helpful for discovering novel fungicides.

New class of hantaan virus inhibitors based on conjugation of the isoindole fragment to (+)-camphor or (-)-fenchone hydrazonesv.

This work presents the design and synthesis of camphor, fenchone, and norcamphor N-acylhydrazone derivatives as a new class of inhibitors of the Hantaan virus, which causes haemorrhagic fever with renal syndrome (HFRS). A cytopathic model was developed for testing chemotherapeutics against the Hantaan virus, strain 76-118. In addition, a study of the antiviral activity was carried out using a pseudoviral system. It was found that the hit compound possesses significant activity (IC50 = 7.6 ± 2 µM) along with low toxicity (CC50 > 1000 µM). Using molecular docking procedures, the binding with Hantavirus nucleoprotein was evaluated and the correlation between the structure of the synthesised compounds and the antiviral activity was established.

(+)-Camphor and (-)-borneol derivatives as potential anti-orthopoxvirus agents.

Although the World Health Organisation had announced that smallpox was eradicated over 40 years ago, the disease and other related pathogenic poxviruses such as monkeypox remain potential bioterrorist weapons and could also re-emerge as natural infections. We have previously reported (+)-camphor and (-)-borneol derivatives with an antiviral activity against the vaccinia virus. This virus is similar to the variola virus (VARV), the causative agent of smallpox, but can be studied at BSL-2 facilities. In the present study, we evaluated the antiviral activity of the most potent compounds against VARV, cowpox virus, and ectromelia virus (ECTV). Among the compounds tested, 4-bromo-N'-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)benzohydrazide 18 is the most effective compound against various orthopoxviruses, including VARV, with an EC50 value of 13.9 µM and a selectivity index of 206. Also, (+)-camphor thiosemicarbazone 9 was found to be active against VARV and ECTV.

Synthesis and antimycobacterial activity of novel camphane-based agents.

A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.

(+)-syn-Benzotriborneol an enantiopure C3-symmetric receptor for water.

(+)-syn-Benzotriborneol forms stable complexes with one molecule of water. This is due to the ability of the host to form three hydrogen bonds with water, to act simultaneously as a hydrogen-bond acceptor and donor, and to a perfect geometrical match between the pair. We report experimental (X-ray and neutron diffraction, VT NMR, DSC, TGA) and stereochemical studies carried out to elucidate and quantify the molecular and thermodynamic aspects of this supramolecular complex.

A non-natural biosynthesis pathway toward 2-methylisoborneol.

The biosynthesis of 2-methylisoborneol was reconstituted by elongation of dimethylallyl diphosphate (DMAPP) with (S)- and (R)-2-methylisopentenyl diphosphate (2-Me-IPP) using farnesyl diphosphate synthase (FPPS), followed by terpene cyclisation. The stereochemical course of the FPPS reaction was studied in detail using stereoselectively deuterated 2-Me-IPP isotopomers.

Oxygen activation by P450(cin): Protein and substrate mutagenesis.

A conserved threonine found in the majority of cytochromes P450 (P450s) has been implicated in the activation of dioxygen during the catalytic cycle. P450(cin) (CYP176A) has been found to be an exception to this paradigm, where the conserved threonine has been replaced with an asparagine. Prior studies with a P450(cin) N242A mutant established that the Asn-242 was not a functional replacement for the conserved threonine but was essential for the regio- and stereocontrol of the oxidation of cineole. To explore further how P450(cin) controls the activation of the dioxygen in the absence of the conserved threonine, two concurrent lines of investigation were followed. Modification of P450(cin) indicated that the Thr-243 was not involved in controlling the protonation of the hydroperoxy species. In addition, the N242T mutant did not enhance the rate and/or efficiency of catalytic turnover of cineole by P450(cin). In parallel experiments, the substrate cineole was modified by removing the ethereal oxygen to produce camphane or 2,2-dimethylbicyclo[2.2.2]octane (cinane). An analogous experiment with P450(EryF) showed that a hydroxyl group on the substrate was vital, and in its absence catalytic turnover was effectively abolished. Catalytic turnover of P450(cin) with either of these alternative substrates (camphane or cinane) revealed that in the absence of the ethereal oxygen there was still a significant amount of coupling of the NADPH-reducing equivalents to the formation of oxidised product. Again the substrate itself was not found to be important in controlling oxygen activation, in contrast to P450(EryF), but was shown to be essential for regio- and stereoselective substrate oxidation. Thus, it still remains unclear how dioxygen activation in the catalytic turnover of cineole by P450(cin) is controlled.

[Resolution of racemic ortho-isobornylphenol into enantiomers and evaluation of their antioxidant activity].

The resolution of the racemic ortho-isobornylphenol into enantiomers via diastereomeric camphanates was carried out. The absolute configuration ofchiral centers of synthesized compounds was established by the single crystal X-ray diffraction method. Antioxidant activity and membrane protective properties of individual enantiomers were studied on the model of H2O2-induced hemolysis of red blood cells.

Salvianic borneol ester reduces ß-amyloid oligomers and prevents cytotoxicity.

CONTEXT: The destabilization of ß-amyloid (Aß) peptide aggregates and the protection of functional cells are the attractive therapeutic strategies for Alzheimer's disease (AD). Some active ingredients of Salvia miltiorrhiza f. alba C.Y.Wu & H.W.Li (Lamiaceae) (SM) have attracted increasing attention for the treatment of neurodegenerative diseases. OBJECTIVE: Salvianic borneol ester (SBE) is a new compound based on SM formulas. The present study was designed to examine the anti-amyloid effects and neuroprotection of SBE in vitro. MATERIALS AND METHODS: The destabilizing effects of SBE and its related compounds (salvianic acid A and borneol) on preformed Aß oligomers were measured by using fluorescence spectroscopy with thioflavin T (ThT) and the destabilizing effects of SBE were further confirmed visually by transmission electron microscopy (TEM). The neuroprotective effects of SBE against hydrogen peroxide (H(2)O(2))-induced toxicity in human neuroblastoma cells (SH-SY5Y) and motor neuron hybridoma cells (VSC 4.1) were shown by MTT assay and morphological observation. RESULTS: SBE showed the most significant destabilizing effect, though the mixture of salvianic acid A and borneol also destabilized Aß1-40 oligomers. The destabilizing activity of salvianic acid A or borneol alone was not significant. SBE destabilized Aß1-40 oligomers in dose- and time-dependent manners and the destabilizing effect could also be seen in the photographs of TEM. Furthermore, SBE could protect SH-SY5Y cells and VSC 4.1 cells against H(2)O(2)-induced toxicity in a dose-dependent manner. DISCUSSION AND CONCLUSION: SBE had the bifunctional activities of anti-amyloid and neuroprotection. It may have therapeutic potential for AD and be an alternative lead compound for developing new drugs against AD.

Bioinspired Durable Antibacterial and Antifouling Coatings Based on Borneol Fluorinated Polymers: Demonstrating Direct Evidence of Antiadhesion.

Substituting natural products for traditional poison-killing antifouling agents is an efficient and promising method to alleviate the increasingly serious ecological crisis and aggravate the loss due to marine biofouling. Herein, the successful synthesis of poly(methyl methacrylate-co-ethyl acrylate-co-hexafluorobutyl methacrylate-co-isobornyl methacrylate) copolymer (PBAF) with borneol monomers and fluorine by a free radical polymerization method is reported. The PBA0.09F coating exhibits outstanding antibacterial and antifouling activity, achieving 98.2% and 92.3% resistance to Escherichia coli and Staphylococcus aureus, respectively, and the number of Halamphora sp. adhesion is only 26 (0.1645 mm2) in 24 h. This remarkable antibacterial and antifouling performance is attributed to the incorporation of fluorine components into the copolymer, which induces a low surface energy and hydrophobicity and the complex molecular structure of the natural nontoxic antifouling agent borneol. In addition, the results showed that the contents of the adhesion-related proteins mfp-3, mfp-5, and mfp-6 were significantly reduced, which proved that natural substances affect the secretion of biological proteins. Importantly, the PBAF coating exhibits excellent environmental friendliness and long-term stability. The antifouling mechanism is clarified, and an effective guide for an environmentally friendly antifouling coating design is proposed.

[Study on natural borneol and synthetic borneol affecting mucosal permeability of gardenia extract].

OBJECTIVE: To observe the influence of natural borneol and synthetic borneol on mucosal permeability of Gardenia extract. METHOD: Taken frog skin as a vitro model to study the vitro mucosal permeation the impacts of the natural borneols and synthetic borneols on the P(app) of the Jasminoidin were studied, and the effect of different borneols on the stability of Jasminoidin were investigated. Compared the 10 h accumulated infiltration rate of each group the effects of influence factors,such as C(Ge), C(B) and rotation speed on P(app) were investigated by using response surface method. RESULT: The P(app) of Jasminoidin of natural borneol and synthetic borneol group were 1.44 fold and 1.77 fold of control group (P < 0.01). For two borneol groups, the results also showed a significant difference too (P < 0.05). Jasminoidin began to degrade about 8 h after the effect of frog skin for control group and synthetic borneol group, but was stable within 12 h for natural borneol group. The accumulated permeation rate of 10 h was same for different borneol groups. It was about 1.3 fold of control group. The C(Ge) had a salinence influence on the P(app) (P < 0.01) and C(B) had a salience influence on time-lag (P < 0.01). CONCLUSION: Both the natural borneol and synthetic borneol can accelerate the permeation of Jasminoidin and the synthetic borneol has stronger effect on the P(app). Both two different borneol can reduce the degradation effect of frog skin to Jasminoidin, but the natural borneol has a better protect effect on it. By using more natural borneol, the mucosal permeability of Gardenia extract can be increased, the time-lag can be reduced, and Jasminoidin has better stability.

Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris.

BACKGROUND AND PURPOSE: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.

Sequential Ni-catalyzed borylation and cross-coupling of aryl halides via in situ prepared neopentylglycolborane.

A procedure for NiCl(2)(dppp)-catalyzed pinacolborylation and neopentylglycolborylation that utilizes in situ prepared inexpensive pinacolborane and neopentylglycolborane is reported. The scope of this reaction was demonstrated with a variety of aryl bromides and iodides. The resulting aryl neopentylglycolboronic esters undergo a NiCl(2)(dppe)-catalyzed cross-coupling with aryl halides, resulting in an extremely efficient and cost-effective method for the synthesis of functional biaryls, dendritic building blocks, and other complex architectures.

Bornyl (3,4,5-trihydroxy)-cinnamate--an optimized human neutrophil elastase inhibitor designed by free energy calculations.

Human neutrophil elastase (HNE), a serine protease, is involved in the regulation of inflammatory processes and controlled by endogenous proteinase inhibitors. Abnormally high levels of HNE can cause degradation of healthy tissues contributing to inflammatory diseases such as rheumatoid arthritis, and also psoriasis and delayed wound healing. In continuation of our research on HNE inhibitors we have used the recently developed binding mode model for a group of cinnamic acid derivative elastase inhibitors and created bornyl (3,4,5-trihydroxy)-cinnamate. This ligand exhibited improved binding affinity predicted by means of free energy calculations. An organic synthesis scheme for the ligand was developed and its inhibitory activity was tested toward the isolated enzyme. Its IC(50) value was found to be three times lower than that of similar compounds, which is in line with the computational result showing the high potential of free energy calculations as a tool in drug development.

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo.

Oxanorbornadiene dicarboxylate (OND) reagents were explored for the purpose of binding and releasing chemical cargos from endogenous circulating serum albumins. ONDs bearing gadolinium chelates as model cargos exhibited variable conjugation efficiencies with albumin in rat subjects that are consistent with the observed reactivity of each linker and their observed stability toward serum hydrolases in vitro. The terminal elimination rate from circulation was dependent on the identity of the OND used, and increased circulation time of gadolinium cargo was achieved for linkers bearing electrophilic fragments designed to react with cysteine-34 of circulating serum albumin. This binding of and release from endogenous albumin highlights the potential of OND linkers in the context of optimizing the pharmacokinetic parameters of drugs or diagnostic agents.

Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB2 receptor antagonists.

During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (Ki in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [(35)S]-GTPγS binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model.

Synthesis and local anesthetic activity of some derivatives of N,N-diethyl-2-(2-alkoxyphenylcarbamoyloxy)bornan-3-ylmethyl-ammonium chlorides.

A series of 8 new esters of 2-alkoxyphenyl-carbamoic acid were synthesized and assayed for local anesthetic activity. All compounds were isolated as hydrochlorides and their structure was proved by 1H-NMR 13C-NMR and IR spectroscopy. The index of anesthetic activity in infiltration and surface anesthesia proved that all prepared compounds are significantly more active than the standard reference compounds, procaine and cocaine, respectively; it is tightly correlated with the length of the alkoxy group. It was found that there is a parabolic relationship between log activity and molecular lipophilicity (as measured by RM). Toxicity of all compounds is within acceptable limits.

Design of novel camphane-based derivatives with antimycobacterial activity.

Although tuberculosis (TB) continues to be one of the leading infectious disease killers globally, it is curable and preventable. Despite the existence of safe, well tolerated and effective drugs used in the TB treatment, the interest in new entities, combinations and regimens increases during the last 10 years. Recently, we reported for a new class of anti-TB agents - camphane-based derivatives with nanomolar activity against Mycobacterium tuberculosis strains. The quantitative structure-activity relationship (QSAR) study on 12 compounds revealed several structural requirements for antimycobacterial activity: two hydrogen bond donors, two or three rings and no large branched substituents. Here, we describe the design of a set of nine novel camphane-based derivatives following these requirements. The compounds were synthesized and tested against M. tuberculosis strain H37Rv. Four of them showed activities in the nanomolar range, significantly higher than the activities in the initial set. The QSAR study based on all 21 derivatives pointed to two main structural requirements for anti-TB activity: two hydrogen bond donors and a side chain with aromatic ring.

Synthesis of dienyl ketones via palladium(II)-catalyzed direct cross-coupling reactions between simple alkenes and vinyl ketones: application to the synthesis of vitamin A1 and bornelone.

An efficient and general method for the synthesis of conjugated dienyl ketones via palladium(II) acetate catalyzed direct cross-coupling between simple alkenes and vinyl ketones is reported. This method has been successfully applied for the synthesis of Vitamin A1 and bornelone.