Economical and Practical Process Development for a Novel Multitarget Tyrosine Kinase Inhibitor Vorolanib

Vorolanib (X-82, CM082) is a novel multitarget tyrosine kinase inhibitor that effectively inhibits the activity of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and FMS-like tyrosine kinase-3 (FLT-3) receptors. Vorolanib is currently accessible in the Chinese market, and its approved indication is combined with Everolimus for patients with advanced renal cell carcinoma (RCC) who have previously failed tyrosine kinase inhibitor (TKI) treatment. Here, we have developed an economical and practical process for Vorolanib, which exhibits low cost, high yield, simple post-treatment, and environmental protection based on extensive investigations into synthesis methods (raw materials, temperature, coupling reagent, solvent, reaction time, post-treatment, etc.). This process was successfully used to prepare Vorolanib with a total yield of 67.1% and a purity of 99.97%, and no chiral degradation occurred during the synthesis. All intermediates were confirmed by ESI-MS and 1H NMR, whereas the target compounds were confirmed by ESI-MS, 1H NMR, and 13C NMR

<i>In Vitro</i> and <i>in Vivo</i> Studies of the Metabolic Activation of 8‑Epidiosbulbin E Acetate

Furanoid 8-epidiosbulbin E acetate (EEA) is a major constituent of herbal medicine Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Our preliminary studies demonstrated that administration of EEA caused acute hepatotoxicity in mice, and the observed toxicity required cytochromes P450-mediated metabolism. Metabolic activation studies of EEA were performed <i>in vitro</i> and <i>in vivo</i>. Microsomal incubations of EEA supplemented with <i>N</i>-acetyl lysine (NAL) and glutathione (GSH) generated six metabolites (M1–M6). M1–M4 were characterized as pyrrole derivatives, and M5 and M6 were pyrrolinones. M2–M6 were detected in bile and/or urine of rats given EEA. Dimethyldioxirane-mediated oxidation of EEA in the presence of NAL and GSH produced M1–M6, all of which were generated in microsomal incubations. The structures of M3 and M6 were confirmed by ¹H and ¹³C NMR. These findings provide evidence for the metabolic activation of EEA to the corresponding <i>cis</i>-enedial intermediate both <i>in vitro</i> and <i>in vivo</i>. Ketoconazole inhibited the microsomal production of the <i>cis-</i>enedial, and P450 3A4 was found to be the primary enzyme involved in the bioactivation of EEA

Quantum Mechanical Prediction and Experimental Verification of Au(I)-Catalyzed Substitution-Controlled Syntheses of 1<i>H</i>‑Pyrido[4,3‑<i>b</i>]indole and Spiro[indoline-3,3′-pyridine] Derivatives

Density functional theory calculations were applied to predict the pathways of gold(I)-catalyzed cycloisomerization of the indole substrates with 1,6-enynes, which were consistent with the ensuing experimental results. The substitution-controlled synthesis led to the formation of 1H-pyrido[4,3-b]indole and spiro[indoline-3,3′-pyridine] derivatives in a tunable way. The reactions had good functional group tolerances, and a possible mechanism was proposed based on the computational and experimental results

Asymmetric Total Synthesis of Neobraclactone C

Asymmetric total synthesis of neobraclactone C was finished for the first time using the convergent synthetic strategy in 22 steps in the longest linear sequence from known materials. The key steps include a steric hindrance/hydrogen bond dual-controlled Heck arylation of α,β-unsaturated ketone to construct hemiketal and cis-alkenyl in one step and a CeCl3-catalyzed tricycle formation

A one-pot synthesis of omarigliptin and its analogues through stabilized <i>beta</i>-amino ketone intermediate

<p>We have discovered a unique stabilization condition for <i>beta</i>-amino ketone <b>7</b>. With compound <b>7</b> as an unprecedented intermediate, omarigliptin <b>1</b> could be prepared in a highly efficient one-pot procedure with good yield. Also with this intermediate <b>7</b>, some analogues of omarigliptin <b>1</b> were readily prepared for the first time.</p

Gold(I)-Catalyzed Angle Strain Controlled Strategy to Furopyran Derivatives from Propargyl Vinyl Ethers: Insight into the Regioselectivity of Cycloisomerization

A unique strategy for the regiospecific synthesis of bicyclic furopyran derivatives has been developed via a gold­(I)-catalyzed propargyl-Claisen rearrangement/6-<i>endo-trig</i> cyclization of propargyl vinyl ethers. The introduction of angle strain into the substrates significantly altered the reaction’s regioselectivity. Insight into the regioselectivity of the cycloisomerization was obtained with density functional theory calculations

Lewis Acid Assisted Electrophilic Fluorine-Catalyzed Pinacol Rearrangement of Hydrobenzoin Substrates: One-Pot Synthesis of (±)-Latifine and (±)-Cherylline

A microwave-irradiated solvent-free pinacol rearrangement of hydrobenzoin substrates catalyzed by a combination of <i>N</i>-fluorobenzenesulfonimide and FeCl₃·6H₂O was developed. Its selectivity was first investigated by density functional theory (DFT) calculations. Then the functional group tolerance was examined by synthesizing a series of substrates designed based on the insight provided by the DFT calculations. The application of the methodology was demonstrated by the efficient one-pot synthesis of (±)-latifine and (±)-cherylline, both are 4-aryltetra­hydro­isoquinoline alkaloids isolated from Amaryllidacecae plants

Gold(I)-Initiated Cycloisomerization/Diels–Alder/Retro-Diels–Alder Cascade Strategy to Biaryls

A unique approach to biaryls was developed on the basis of propargyl vinyl ethers and dienophiles substrates via a gold­(I)-initiated cycloisomerization/Diels–Alder/retro-Diels–Alder cascade reaction. The scope and mechanism of the reaction were investigated on the basis of a series of synthetic substrates, control experiments, and DFT calculations

Collective Syntheses of 2‑(3-Methylbenzofuran-2-yl)phenol-Derived Natural Products by a Cascade [3,3]-Sigmatropic Rearrangement/Aromatization Strategy

A cascade [3,3]-sigmatropic rearrangement/aromatization strategy to the synthesis of 2-(3-methylbenzofuran-2-yl)­phenol derivatives was developed and applied to the collective syntheses of seven 2-arylbenzofuran-containing natural products, namely glycybenzofuran, glycyuralin E, lespedezol A₁, puerariafuran, 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid, coumestrol, and 4′-<i>O</i>-methylcoumestrol. Among them, the total syntheses of glycybenzofuran, glycyuralin E, puerariafuran, 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid, and 4′-<i>O</i>-methylcoumestrol were reported for the first time. The practicality of this novel strategy in preparation of the key intermediates was demonstrated by performing the reaction on gram scale and by synthesizing a series of natural products with 2-(3-methylbenzofuran-2-yl)­phenol scaffolds in a common strategy

<b>CJ</b>_<b>2</b>: A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane

Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ2-reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ2 could arouse the immune system and promote CD8+ T cell infiltration. Meanwhile, CJ2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response