Reduction-induced hapticity increase in a silacycle-bridged biaryl-based ligand coordinated to an iron center.

An Fe(II) bromide complex supported by a bidentate phosphine ligand and an η1(C)-coordinated six-membered silacycle-bridged biphenyl-based ligand is converted upon reduction into an Fe(I) complex in which the hapticity of the silacycle-based ligand increases from η1 to η5.

Iron(II) Complex with a Silacycle-Bridged Biaryl-Based Ligand.

Treatment of 2,6-dimethyl-1,1'-biphenyl-substituted chlorosilane with potassium followed by FeBr2/TMEDA led to the formation of an iron(II) monobromide complex supported by a TMEDA ligand and a carbanion-based ligand containing a six-membered silacycle-bridged biphenyl skeleton. The obtained complex crystallized as a racemic mixture of (Sa, S) and (Ra, R) forms, in which the dihedral angle of the two phenyl rings of the biphenyl moiety was ∼43°.

Otitis externa caused by Malassezia slooffiae complicated with mastoiditis: A case report.

Herein, we report a case of otitis externa caused by Malassezia slooffiae complicated with mastoiditis. A 70-year-old male complained of fever and severe otorrhea from left external auditory canal 2 months after undergoing a craniotomy to remove a hematoma. He had right-sided paralysis and undertook bed rest. Brain computed tomography revealed continuous fluid accumulation in the left mastoid air cells and middle ear from left external auditory canal in addition to leukocytosis and increased C-reactive protein level. The tympanic membrane was severely swelling. These results indicated the presence of otitis media and mastoiditis. Otorrhea culture showed large amounts of M. slooffiae. The administration of liposomal amphotericin B (L-AMB), the irrigation of external auditory canal with normal saline, and the application of topical ketoconazole ointment were started. The administration of L-AMB for 8 weeks and voriconazole, which was switched from L-AMB, for 4 weeks ameliorated his infection and he was transferred to another hospital to receive rehabilitation. From these results and his clinical course, the diagnosis of otitis externa caused by Malassezia slooffiae complicated with mastoiditis was made. And the possibility of the contamination by M. slooffiae was very low. Clinicians should be aware that M.slooffiae can provoke otological infections since M. slooffiae is the most common Malassezia sp. in external auditory canal.

Tetracyclic Truncated Analogue of the Marine Toxin Gambierol Modifies NMDA, Tau, and Amyloid ß Expression in Mice Brains: Implications in AD Pathology.

Gambierol and its two, tetra- and heptacyclic, analogues have been previously proved as promising molecules for the modulation of Alzheimer's disease (AD) hallmarks in primary cortical neurons of 3xTg-AD fetuses. In this work, the effect of the tetracyclic analogue of gambierol was tested in vivo in 3xTg-AD mice (10 months old) after 1 month of weekly treatment with 50 µg/kg. Adverse effects were not reported throughout the whole treatment period and no pathological signs were observed for the analyzed organs. The compound was found in brain samples after intraperitoneal injection. The tetracyclic analogue of gambierol elicited a decrease of amyloid ß1-42 levels and a dose-dependent inhibition of ß-secretase enzyme-1 activity. Moreover, this compound also reduced the phosphorylation of tau at the 181 and 159/163 residues with an increase of the inactive isoform of the glycogen synthase kinase-3ß. In accordance with our in vitro neuronal model, this compound produced a reduction in the N2A subunit of the N-methyl-d-aspartate (NMDA) receptor. The combined effect of this compound on amyloid ß1-42 and tau phosphorylation represents a multitarget therapeutic approach for AD which might be more effective for this multifactorial and complex neurodegenerative disease than the current treatments.

Diastereoselective Ring-Closing Metathesis as a Means to Construct Medium-Sized Cyclic Ethers: Application to the Synthesis of a Photoactivatable Gambierol Derivative.

This paper describes a concise synthesis of six- to eight-membered α,α'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding α-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered α,α'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

Evaluation of gambierol and its analogs for their inhibition of human Kv1.2 and cytotoxicity.

Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel Kv1.2 (hKv1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from -80mV to 40mV. The IC50 values for the three compounds were 0.75±0.15nM, 7.6±1.2nM, and 28±4.0nM (the mean±SEM, n=3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hKv1.2. The IC50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95±7.1µM, 6.5±0.8µM (the mean±SEM, n=3), and >100µM (n=3), respectively, whereas those in the CHO cells stably expressing hKv1.2 were 78±5.8µM, 6.0±1.0µM (the mean±SEM, n=3), and >100µM (n=3). These results suggested that cytotoxicity is not triggered by inhibition of the human Kv1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells.

Stereoselective synthesis of medium-sized cyclic ethers: application of C-glycosylation chemistry to seven- to nine-membered lactone-derived thioacetals and their sulfone counterparts.

Stereoselective synthesis of α,α'-substituted medium-sized cyclic ethers has been achieved by means of nucleophilic substitution of the corresponding lactone-derived thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the corresponding sulfones followed by treatment with an appropriate organometallic species such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of a variety of α,α'-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.

Concise synthesis and biological assessment of (+)-neopeltolide and a 16-member stereoisomer library of 8,9-dehydroneopeltolide: identification of pharmacophoric elements.

We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.

Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study.

The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 µg/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases.

Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-ß and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications.

Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K(v) channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (K(v)) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aß) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K(+) currents, a reduction in the extra- and intracellular levels of Aß, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K(v) channels as well as the molecular mechanism of Aß metabolism modulated by NMDA receptors.

Highly efficient synthesis of medium-sized lactones via oxidative lactonization: concise total synthesis of isolaurepan.

A catalytic amount of TEMPO in the presence of PhI(OAc)(2) effected oxidative lactonization of 1,6- and 1,7-diols, directly affording seven- and eight-membered lactones, respectively, in good yields.