Strategies and Lessons Learned from Total Synthesis of Taxol.

Taxol (paclitaxel), the most well-known taxane diterpenoid, is the best-selling natural-source anticancer drug ever produced and one of the most common prescriptions in the treatment of breast, lung, and ovarian cancers, saving countless lives around the world. Structurally, Taxol possesses a highly oxygenated [6-8-6-4] core bearing 11 stereocenters, seven of which are contiguous chiral centers. Moreover, the extremely strained bicyclo[5.3.1] undecane ring system with a bridgehead double bond is a unique structural feature. All these features make Taxol a highly challenging synthetic target. Tremendous synthetic efforts from more than 60 research groups around the world have already culminated in ten total syntheses and three formal syntheses, as well as more than 60 synthetic model studies of Taxol. This review is intended to provide a long-overdue appraisal of the great achievements in the total syntheses of Taxol reported in the last few decades. In doing so, we summarize the development of synthesis toward Taxol from 1994 to 2022, including the evolution of synthetic strategy for accessing this complex molecular scaffold and key lessons learned from such endeavors. Finally, we briefly discuss the future of the research in this area.

Recent Advances in the Total Synthesis of Natural Products Containing Eight-Membered Carbocycles (2009-2019).

Natural products containing eight-membered carbocycles constitute a class of structurally intriguing and biologically important molecules such as the famous diterpenes taxol and vinigrol. Such natural products are being increasingly investigated because of their fascinating architectural features and potent medicinal properties. However, synthesis of natural products with cyclooctane moieties has proved to be highly challenging. This review highlights the recently completed total syntheses of natural products with eight-membered carbocycles with a focus on strategic considerations. A collection of 27 representative studies from the literature covering the decade from 2009 to 2019 is described in chronological order with relevant studies grouped together, including syntheses of the same natural product by different research groups using different strategies. Finally, a summary and outlook including a discussion of the major features of each strategy used in the syntheses are presented. This review illustrates the diversity and creativity in the elegant synthetic designs of eight-membered carbocycles. We hope this review will provide timely illumination and beneficial guidance for future synthetic efforts for organic chemists who are interested in this area.

Ruthenium-Catalyzed Metathesis Cascade Reactions in Natural Products Synthesis.

In this account, we provide a brief summary of recent developments in ruthenium-catalyzed metathesis cascade reactions towards the total synthesis of natural products. We also highlight recent progress from our own laboratory regarding the synthesis of securinega alkaloids and humulanolides, which has resulted in the development of novel ruthenium-catalyzed metathesis cascade reactions. Inspired and guided by the pioneering and elegant research conducted in this area, we developed a regio-controlled relay dienyne metathesis cascade reaction and a cyclobutene-promoted RCM/ROM/RCM cascade reaction for the synthesis of securinega alkaloids and humulanolides, respectively.

Catalytic Enantioselective Total Synthesis of Hypocrolide A.

The first and catalytic enantioselective total synthesis of hypocrolide A (>99% ee) in 12 steps, as well as other botryanes, is described. The absolute configurations of these compounds have been unambiguously confirmed or reassigned accordingly. The key reactions in this study include an unusual rhodium-catalyzed intramolecular [4 + 2] cycloaddition and a biomimetic oxidative [3 + 2] cycloaddition based on our revised biogenetic pathway.

Lipidomics investigation of reversal effect of glycyrrhizin (GL) towards lithocholic acid (LCA)-induced alteration of phospholipid profiles.

CONTEXT: Glycyrrhizin (GL), the major ingredient isolated from licorice, exerts multiple pharmacological activities. OBJECTIVE: To elucidate the protective mechanism of GL towards lithocholic acid (LCA)-induced liver toxicity using lipidomics. MATERIALS AND METHODS: GL (200 mg/kg) dissolved in corn oil was treated intraperitoneally for 7 d. On the 4th day, 200 mg/kg LCA was used to treat mice (i.p., twice daily) for another 4 d. The protective role of GL towards LCA-induced liver toxicity was investigated through evaluating the liver histology and the activity of alanine transaminase (ALT). The complete lipid profile was employed using UFLC-Triple TOF MS-based lipidomics. RESULTS: Intraperitoneal (i.p.) administration of 200 mg/kg GL can significantly protect LCA-induced liver damage, indicated by alleviated histology alteration and prevention of the ALT elevation. Lipidomics analysis can well separate the control group from LCA-treated group, and three lipid components were major contributors, including LPC 16:0, LPC 18:0, and LPC 18:2. GL treatment can significantly prevent LCA-induced reduction of these three lipid compounds, providing a new explanation for GL's protection mechanism towards LCA-induced liver toxicity. DISCUSSION AND CONCLUSION: The recent study highlights the importance of lipidomics in elucidating the therapeutic mechanism of herbs.

Collective synthesis of humulanolides using a metathesis cascade reaction.

A new method has been developed for the concise and asymmetric synthesis of seven humulanolides in 5-7 steps without the need for protecting groups. Notably, the challenging 11-membered ring and bridged butenolide moieties in asteriscunolide D and 6,7,9,10-tetrahydroasteriscunolide were introduced in one step using a ring-opening/ring-closing metathesis cascade reaction. Asteriscunolide D was used as a versatile synthetic precursor to prepare asteriscunolides A-C via a photoinduced isomerization reaction, asteriscanolide via a unique transannular Michael reaction, and 6,7,9,10-tetradehydroasteriscanolide via a transannular Morita-Baylis-Hillman-type reaction. The unique bicyclo[6.3.0]undecane core was introduced diastereoselectively.

Targeted metabolomic study indicating glycyrrhizin's protection against acetaminophen-induced liver damage through reversing fatty acid metabolism.

The present study aimed to give a short report on a possible mechanism of glycyrrhizin to acetaminophen-induced liver toxicity. Seven-day intraperitoneal administration of glycyrrhizin (400 mg/kg/day) to 2- to 3-month-old male C57BL/6N mice (mean weight 27 g) significantly prevents acetaminophen-induced liver damage, as indicated by the activity of alanine transaminase and aspartate aminotransferase. Metabolomics analysis and principal component analysis (PCA) using ultra-fast liquid chromatography coupled to triple time-of-flight mass spectrometer were performed. PCA separated well the control, glycyrrhizin-treated, acetaminophen-treated, and glycyrrhizin+acetaminophen-treated groups. Long-chain acylcarnitines were listed as the top ions that contribute to this good separation, which include oleoylcarnitine, palmitoylcarnitine, palmitoleoylcarnitine, and myristoylcarnitine. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by acetaminophen administration. In conclusion, this metabolomic study indicates a significant glycyrrhizin protection effect against acetaminophen-induced liver damage through reversing fatty acid metabolism.

Biotransformation of glucoaurantio-obtusin towards aurantio-obtusin increases the toxicity of irinotecan through increased inhibition towards SN-38 glucuronidation.

The present study aims to investigate the influence of irinotecan's toxicity by the biotransformation of glucoaurantio-obtusin to aurantio-obtusin. Intraperitoneal administration (i.p.) of 100 mg/kg aurantio-obtusin significantly increased the toxicity of irinotecan, but the i.p. administration of 100 mg/kg glucoaurantio-obtusin showed negligible influence towards irinotecan's toxicity. Furthermore, the mechanism was explained through determining the inhibition potential of glucoaurantio-obtusin and aurantio-obtusin towards the glucuronidation metabolism of SN-38 that has been regarded to be the major active product responsible for the toxicity of irinotecan. The results showed that aurantio-obtusin exhibited strong competitive inhibition towards the glucuronidation of SN-38, but negligible inhibition potential of glucoaurantio-obtusin towards SN-38 glucuronidation was observed. These results showed that biotransformation of glucoaurantio-obtusin towards aurantio-obtusin increased the toxicity of irinotecan through increased inhibition of SN-38 glucuronidation.

Asymmetric, protecting-group-free total synthesis of (+)-caribenol A.

Caribenol Queen: A new asymmetric, protecting-group-free synthesis of the marine tetracyclic diterpenoid (+)-caribenol A (1) has been achieved. The enantioselective synthesis employed (S)-methyl 1-methyl-2-oxocyclopent-3-enecarboxylate as a chiral scaffold, and an intramolecular Diels-Alder (IMDA) reaction of substrate 3 afforded the [5.7.6] tricyclic core in compound 2.

Asymmetric total synthesis of caribenol A via an intramolecular Diels-Alder reaction.

A total synthesis of the caribenol A (1), a novel natural product with an intriguing tetracyclic framework, has been achieved. The synthesis features an intramolecular Diels-Alder (IMDA) reaction for the facile construction of the tricyclic [5-7-6] skeleton of caribenol A (1) and a biomimetic oxidation reaction for the formation of the 2-hydroxyfuran-2(5H)-one motif of caribenol A (1) as key steps. This synthetic approach also reveals that the sp(2) carbon at C(2) in substrate 8 is a critical factor for the formation of the tricyclic [5-7-6] skeleton in 7.

In vitro characterization of glucuronidation of vanillin: identification of human UDP-glucuronosyltransferases and species differences.

Vanillin is a food flavoring agent widely utilized in foods, beverages, drugs, and perfumes and has been demonstrated to exhibit multiple pharmacological activities. Given the importance of glucuronidation in the metabolism of vanillin, the UDP-glucuronosyltransferase conjugation pathway of vanillin was investigated in this study. Vanillin glucuronide was identified by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and a hydrolysis reaction catalyzed by ß-glucuronidase. The kinetic study showed that vanillin glucuronidation by HLMs and HIMs followed Michaelis-Menten kinetics and the kinetic parameters were as follows: 134.9 ± 13.5 µM and 81.3 ± 11.3 µM for K(m) of HLMs and HIMs, 63.8 ± 2.0 nmol/min/mg pro and 13.4 ±2.0 nmol/min/mg pro for Vmax of HLMs and HIMs. All UDP-glucuronosyltransferase (UGT) isoforms except UGT1A4, 1A9, and 2B7 showed the capability to glucuronidate vanillin, and UGT1A6 exerted the higher V(max)/K(m) values than other UGT isoforms for the glucuronidation of vanillin when assuming expression of isoforms is similar in recombinant UGTs. Kinetic analysis using liver microsomes from six studied speices indicated that vanillin had highest affinity for the monkey liver microsomes enzyme (K(m) = 25.6 ± 3.2 µM) and the lowest affinity for the mice liver microsomes enzyme (K(m) = 149.1 ± 18.4 µM), and intrinsic clearance was in the following order: monkey > dog > minipig > mice > rat ~ human. These data collectively provided important information for understanding glucuronidation of vanillin.

Expression of seven gastric cancer-associated genes and its relevance for Wnt, NF-kappaB and Stat3 signaling.

The aim of the current study was to profile c-Myc, standard CD44 (CD44s), CD44v6, cyclin D1, survivin, MMP-7 and VEGF expression patterns in different gastric samples and to elucidate their relevance for Wnt, NF-kappaB and/or Stat3 activation using multiple experimental approaches. The results revealed that 87.1% (27/31) of gastric cancers and 8.7% (2/23) of noncancerous lesions (chronic gastritis and intestinal metaplasia) showed Wnt activation (Wnt(+)) that was closely related to the expression of the seven genes. Some Wnt(-) noncancerous lesions also expressed the above-mentioned genes, higher frequencies of survivin (7/8), VEGF (7/8), cyclin D1 (6/8) and c-Myc (5/8) but not CD44s (2/8), CD44v6 (3/8) and MMP-7 (2/8) being detected in the NF-kappaB(+) samples. Stat3 was activated in 37/54 gastric tissues, and in 3/4 VEGF, 4/6 c-Myc, 4/8 survivin, 2/4 MMP-7, 1/2 CD44v6, and 4/9 cyclin D1(+) but Wnt(-)/NF-kappaB(-) samples. These findings showed a close correlation in GCs between Wnt, NF-kappaB and Stat3 signaling and expression of the seven genes, the importance of NF-kappaB and Stat3 activation in regulating c-Myc, survivin, cyclin D1 and VEGF in noncancerous lesions, and the potential coordinative effects of these three signalings on GC formation presumably by promoting the transcription of their common target genes.