Three-Component, Diastereoselective Prins–Ritter Reaction for <i>cis</i>-Fused 4‑Amidotetrahydropyrans toward a Precursor for Possible Neuronal Receptor Ligands

Here, we report an unprecedented, highly diastereoselective Prins–Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-<i>cis</i>-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42–97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure–activity relationships of biologically active small molecules

Preoperative prognostic factors for disease-free survival with small adenocarcinomas (≤3 cm).

<p>Logistic regression test (Univariate analyses).</p><p>LD: diameter using lung window setting, MD: diameter using mediastinal window setting, RFS: recurrence-free survival, TDR: tumour disappearance ratio (TDR  = 1− MD/LD), CEA: carcinoembryonic antigen, cN: preoperative nodal status, CI: confidence interval.</p><p>Preoperative prognostic factors for disease-free survival with small adenocarcinomas (≤3 cm).</p

Preoperative factors associated with lymph node metastasis in small adenocarcinoma (≤3 cm).

<p>Logistic regression test (Univariate analyses).</p><p>LD: diameter by lung window setting, MD: diameter by mediastinal window setting, TDR: tumour disappearance ratio (TDR  = 1− MD/LD), CEA: carcinoembryonic antigen, cN: preoperative nodal status, CI: confidence interval, LN: lymph node.</p><p>Preoperative factors associated with lymph node metastasis in small adenocarcinoma (≤3 cm).</p

Receiver operating characteristic analyses for recurrence.

<p>Tumour dimension was evaluated using lung window (LD) and mediastinal window (MD) settings. TDR: tumour disappearance ratio (TDR  = 1− MD/LD). Allow indicated a value at 100% sensitivity.</p

Incidence of lymphatic vessel, vascular vessel or pleural invasion in small adenocarcinomas according to tumour dimension using mediastinal window (MD) settings.

<p>A black bar showed a patient with invasion to any of lymphatic vessel, vascular vessel or pleura, and a gray bar showed a patient without any of them.</p

The 5-year disease-free survival curve according to tumour dimension using mediastinal window (MD) settings.

<p>Tumour dimension was evaluated using mediastinal window (MD) settings. One case with MD 9 mm showed recurrence and the case is the smallest in MD among all.</p

Receiver operating characteristic analyses for lymph node metastasis.

<p>Tumour dimension was evaluated using lung window (LD) and mediastinal window (MD) settings. TDR: tumour disappearance ratio (TDR  = 1− MD/LD), CEA: carcinoembryonic antigen. Allow indicated a value at 100% sensitivity.</p

Preoperative factors associated with pleural, lymphatic and vascular invasion in small adenocarcinomas (≤3 cm).

<p>Logistic regression test (Univariate analyses).</p><p>LD: diameter by lung window setting, MD: diameter by mediastinal window setting, TDR: tumour disappearance ratio (TDR  = 1− MD/LD), CEA: carcinoembryonic antigen, cN: preoperative nodal status, CI: confidence interval, ly: lymphatic vessels, v: vascular vessels, pl: pleura.</p><p>Preoperative factors associated with pleural, lymphatic and vascular invasion in small adenocarcinomas (≤3 cm).</p

Studies on Aculeines: Synthetic Strategy to the Fully Protected Protoaculeine B, the <i>N</i>‑Terminal Amino Acid of Aculeine B

A synthetic strategy for accessing protoaculeine B (<b>1</b>), the <i>N</i>-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of <b>1</b> with a 12-mer poly­(propanediamine). The synthesis of mono­(propane­diamine) analog <b>2</b>, as well as core amino acid <b>3</b>, was demonstrated by this strategy. New amino acid <b>3</b> induced convulsions in mice; however, compound <b>2</b> showed no such activity

Characteristics of patients with left upper lobe non-small cell cancer.

<p>Characteristics of patients with left upper lobe non-small cell cancer.</p