Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between ß-oxo esters and ß-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Highly modified cephalotane-type diterpenoids from Cephalotaxus fortunei var. alpina and C. sinensis.

Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis, leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A-F (1-6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13-p-hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents.

Diterpenolignans and cephalotane diterpenoids from Cephalotaxus oliveri mast. with antitumor activity.

Four undescribed naturally diterpenolignans, and two cephalotane diterpenoids, along with seven known compounds, including two pairs of enantiomers, were isolated from the twigs and leaves of Cephalotaxus oliveri Mast. Their structures were elucidated via spectroscopic data interpretation, chiral-phase HPLC analysis, NMR calculations, and electronic circular dichroism analysis. All the isolated compounds were evaluated for their cytotoxic activities against three kinds of human tumor cell lines. Among them, compound 8 exhibited the most potent activities against MCF-7, HepG2 and A549 cell lines with IC50 values of 2.83, 4.75 and 2.77 µM, respectively.

Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M-N, P.

The asymmetric total syntheses of cephalotaxus C19 diterpenoids, bearing a unique cycloheptene A ring with a chiral methyl group at C-12, were disclosed based on a universal strategy. Six members, including cephinoid P, cephafortoid A, 14-epi-cephafortoid A and fortalpinoids M-N, P, were accomplished for the first time. The concise approach relies on two crucial steps: (1) a Nicholas/Hosomi-Sakurai cascade reaction was developed to efficiently generate the cycloheptene ring bearing a chiral methyl group; (2) an intramolecular Pauson-Khand reaction was followed to facilitate the construction of the complete skeleton of target molecules. Our studies provide a new strategy for the synthetic analysis of cephalotaxus diterpenoids and structurally related polycyclic natural products.

[Lignans from stems and leaves of Cephalotaxus fortunei (â ¡)].

The present study aimed to explore the chemical constituents from the stems and leaves of Cephalotaxus fortunei. Seven lignans were isolated from the 75% ethanol extract of C. fortunei by various chromatographic methods, including silica gel, ODS column chromatography, and HPLC. The structures of the isolated compounds were elucidated according to physicochemical properties and spectral data. Compound 1 is a new lignan named cephalignan A. The known compounds were identified as 8-hydroxy-conidendrine(2), isolariciresinol(3), leptolepisol D(4), diarctigenin(5), dihydrodehydrodiconiferyl alcohol 9'-O-ß-D-glucopyranoside(6), and dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucopyranoside(7). Compounds 2 and 5 were isolated from the Cephalotaxus plant for the first time.

Characteristics of Cephalotaxus fortunei kernel oil and its digestion behaviors.

Cephalotaxus fortunei, a potential underutilized oil resource, contains various active ingredients that exert positive effects on human health. In the present study, characteristics of C. fortunei kernel oil and its digestion properties were systematically investigated. Results indicated that C. fortunei kernels contained high oil content (64.59%), of which over 90% was triacylglycerols (TAGs). The kernel oil was rich in oleic acid (C18:1n-9, 42.88%), linoleic acid (C18:2n-6, 31.05%), and sciadonic acid (C20:3n-6, 10.78%). The kernel oil also contained some beneficial fat-soluble nutrients, such as tocopherols (143 mg/kg) and phytosterols (1474 mg/kg). Thirty-five kinds of TAGs were identified, among which O-O-L (17.96%), O-O-O (12.12%), L-L-O (11.79%), O-L-Et (8.59%), and O-O-Et (8.76%) were the most abundant. In vitro digestion experiments showed that after 120 min of small intestine digestion, the maximum FFAs release level of the kernel oil was 75.02%, which was lower than that of soybean oil (89.63%).

Molecular Networking Accelerated Discovery of Biflavonoid Alkaloids from Cephalotaxus sinensis.

Four undescribed biflavonoid alkaloids, sinenbiflavones A-D, were isolated from Cephalotaxus sinensis using a MS/MS-based molecular networking guided strategy. Their structures were elucidated by series of spectroscopic methods (HR-ESI-MS, UV, IR, 1D, and 2D NMR). Sinenbiflavones A-D are the first examples of amentoflavone-type (C-3'-C-8'') biflavonoid alkaloids. Meanwhile, sinenbiflavones B and D are the unique C-6-methylated amentoflavone-type biflavonoid alkaloids. Sinenbiflavone D showed weak SARS-CoV-2 3CLpro inhibitory activity with 43 % inhibition rate at 40 µM.

Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer Cephalotaxus hainanensis.

Cephalotaxines harbor great medical potential, but their natural source, the endemic conifer Cephalotaxus is highly endangered, creating a conflict between biotechnological valorization and preservation of biodiversity. Here, we construct the whole biosynthetic pathway to the 1-phenethylisoquinoline scaffold, as first committed compound for phenylethylisoquinoline alkaloids (PIAs), combining metabolic modeling, and transcriptome mining of Cephalotaxus hainanensis to infer the biosynthesis for PIA precursor. We identify a novel protein, ChPSS, driving the Pictet-Spengler condensation and show that this enzyme represents the branching point where PIA biosynthesis diverges from the concurrent benzylisoquinoline-alkaloids pathway. We also pinpoint ChDBR as crucial step to form 4-hydroxydihydrocinnamaldehyde diverging from lignin biosynthesis. The elucidation of the early PIA pathway represents an important step toward microbe-based production of these pharmaceutically important alkaloids resolving the conflict between biotechnology and preservation of biodiversity.

Lignans from stems and leaves of Cephalotaxus fortunei (Ⅱ) / 中国中药杂志

The present study aimed to explore the chemical constituents from the stems and leaves of Cephalotaxus fortunei. Seven lignans were isolated from the 75% ethanol extract of C. fortunei by various chromatographic methods, including silica gel, ODS column chromatography, and HPLC. The structures of the isolated compounds were elucidated according to physicochemical properties and spectral data. Compound 1 is a new lignan named cephalignan A. The known compounds were identified as 8-hydroxy-conidendrine(2), isolariciresinol(3), leptolepisol D(4), diarctigenin(5), dihydrodehydrodiconiferyl alcohol 9'-O-β-D-glucopyranoside(6), and dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside(7). Compounds 2 and 5 were isolated from the Cephalotaxus plant for the first time.

Cytotoxic alkaloids from the twigs and leaves of Cephalotaxus sinensis.

Twelve new Cephalotaxus alkaloids (1-12) and nine known analogues (13-21) were isolated and identified from the twigs and leaves of Cephalotaxus sinensis. The structures of the new compounds (1-12) were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Cephalosine H (8) is the third example of an alkaloid containing the cephalolancine skeleton. Cephalosines J and K (10 and 11) are the rare natural Δ(2)1-alkene-6-hydroxyl homoerythrina-type alkaloids isolated from the Cephalotaxus genus. The racemization of cephalotaxine-type alkaloids is discussed. Alkaloids 6, 7, 11, 16, 18 and 19 exhibited broad and potent cytotoxicities against five human cancer cell lines, with IC50 values ranging from 0.053 to 10.720 µM, highlighting these compounds as promising leads for the development of new antitumor agents.

Cephalotane-type C20 diterpenoids from Cephalotaxus fortunei var. alpina.

Seventeen new cephalotane-type diterpenoids, fortalides A-Q (1-17), along with five known analogues, were isolated from the seeds of Cephalotaxus fortunei var. alpina. Their structures were determined by extensive spectroscopic methods, as well as electronic circular dichroism (ECD) and X-ray crystallographic data analyses. Some isolates exhibited unusual structural features that were first found in cephalotane-type diterpenoids, such as the occurrence of the 7-oxabicyclo[4.1.1]octane moiety in 14 and 15 and the cis-arrangement of 3-OH and Me-19 in 9. Besides, the antiplasmodial activity of these compounds was evaluated in this study.

Cephalotaxine-type and homoerythrina-type alkaloids with antiproliferative effects from Cephalotaxus fortunei.

Twenty-two cephalotaxine-type and ten homoerythrina-type alkaloids, including seven previously undescribed ones, were isolated from the twigs and leaves and the seed kernels of Cephalotaxus fortunei. Their structures were established by spectroscopic analysis, single crystal X-ray diffraction, and ECD calculation methods. Cephalofortunine A ß-N-oxide (1) is the first nitrogen-oxidized homoerythrina-type alkaloid. The isolated compounds were evaluated for their in vitro antiproliferative effects against two human leukemia cell lines (THP-1 and K562). All compounds showed different levels of antiproliferation in THP-1 and K562 cells with GI50 values of 0.24-29.55 µM. Hainanensine (31) was the most active against two cancer cell lines with GI50 values of 0.24 ± 0.07, and 0.29 ± 0.01 µM, respectively.

[Two novel cephalotaxine-type alkaloids from Cephalotaxus sinensis].

Silica gel, octadecyl-silica(ODS), Sephadex LH-20, and semi-preparative high performance liquid chromatography(HPLC) was performed to isolate nine cephalotaxine-type alkaloids from Cephalotaxus sinensis: 8-oxodeoxyharringtonine(1), 8-oxonordeoxyharringtonine(2), cephafortunine A(3), 8-oxocephalotaxine(4), deoxyharringtonine(5), acetylcephalotaxine(6), cephalotaxine(7), epicephalotaxine(8), and cephalotaxinone(9). Compounds 1 and 2 were identified for the first time and their structures were determined by high-resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), nuclear magnetic resonance(NMR), and electronic circular dichroism(ECD). Compounds 1-3 and 5 significantly inhibited the transcription of nuclear factor kappa B(NF-κB), with the half-maximal inhibitory concentration(IC_(50)) of(3.91±0.70),(2.99±0.45),(7.84±0.51), and(1.46±0.17) µmol·L~(-1), respectively.

Cephalotaxine homologous alkaloids from seeds of Cephalotaxus oliveri Mast.

Six undescribed isoquinoline alkaloids, named as cephaloliverines A-F, were isolated from the seeds of Cephalotaxus oliveri. They were identified by NMR and MS spectroscopic data analyses, combined with the time-dependent density functional theory ECD calculation for cephaloliverines A and B and also by X-ray crystal diffraction for cephaloliverine E. Biosynthetic considerations suggest that cephaloliverines A-D are homologous of cephalotaxine-, homoerythrina- and Erythrina-type alkaloids. The performed bioassay revealed no cytotoxic activity against cancer cells and no neuroprotective properties on HEI-OC-1 cells model.

Cephaloliverols A and B, two sterol-hybrid meroterpenoids from Cephalotaxus oliveri.

Cephaloliverols A (1) and B (2), two meroterpenoids based on a sterol and an abietane diterpene possessing a dioxane ring, were isolated from the twigs and leaves of Cephalotaxus oliveri. Their structures were established by spectroscopic analysis and quantum chemical calculation. 1 and 2 represent the first sterol-hybrid meroditerpenoids. The two compounds and their precursors decreased NO production in a dose-dependent manner in LPS-stimulated RAW 264.7 macrophages.

Abietane diterpenes from the twigs and leaves of Cephalotaxus oliveri Mast. with antitumor activity.

Twenty one abietane diterpenes were isolated from Cephalotaxus oliveri Mast. The structures of 7 undescribed diterpenoids, named cephaloliverins A-G, were elucidated via spectroscopic data interpretation and electronic circular dichroism (ECD) analysis. The isolated diterpenoids were evaluated for their cytotoxicity against three kinds of human tumor cell lines (MCF-7, HepG2, and A549). Metaglyptin A was the most active with IC50 values of 16.34, 15.63 and 21.33 µM and was further investigated for colony formation and apoptosis in HepG2 cells.

Biflavonoids from the twigs and leaves of Cephalotaxus oliveri Mast. and their α-glucosidase inhibitory activity.

Three new biflavonoids, umcephabiovins C - E (1 - 3), along with fourteen known compounds were isolated from the twigs and leaves of Cephalotaxus oliveri. Their structures and configurations were elucidated by UV, IR, NMR, ECD, and HR-ESI-MS spectra. Compounds 1 - 3 exhibited significant α-glucosidase inhibitory activity with IC50 values of 7.05 ± 2.66, 24.45 ± 4.73, and 1.84 ± 1.14 µM, respectively. Compound 11 showed moderate cytotoxicity against the BaF3/T315I cell line.

Progress in structure, synthesis and biological activity of natural cephalotane diterpenoids.

The Cephalotaxus genus is well-known owing to the numerous complex, biologically relevant natural products that can be obtained from its constituent species. The successful identification of various Cephalotaxus alkaloids and natural, structurally diverse cephalotane diterpenoids that exhibit antitumor activities and excellent pharmacological properties has encouraged the discovery of previously undescribed compounds from this genus. The present review summarizes the different strategies for the total synthesis of cephalotane diterpenoids as well as their diverse chemical structures, antitumor activities, structure-activity relationships (SARs), and biosynthetic pathways.

Cephalotaxine-type alkaloids with antiproliferation effects from the branches and leaves of Cephalotaxus fortunei var. alpina.

Eight cephalotaxine-type alkaloids (1-8), including two new compounds cephafortunines A and B (1-2), were isolated from the branches and leaves of Cephalotaxus fortunei var. alpina. Their structures were identified by a series of spectroscopic methods (MS, UV, IR, 1D, and 2D NMR) and comparison with the reported data of known analogs. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations. 1-8 were evaluated for their in vitro antiproliferation effects against two human leukemia cell lines (U937 and HL-60). All compounds showed different levels of antiproliferation effects against U937 cells with GI50 values of 4.21-23.70 µM. 4 and 5 were the most active against U937 cells with GI50 values of 4.21 and 6.58 µM and against HL-60 cells with GI50 values of 6.66 and 6.70 µM, respectively. 4 and 5 arrested HL-60 cell cycle in G0/G1 phase.

Cephalotaxine-type alkaloids from the seeds of Cephalotaxus fortunei and their cytotoxic activities.

Six new Cephalotaxus alkaloids, including five cephalotaxine-type alkaloids, and one homoerythrina-type alkaloid, along with six known analogues, were isolated from the seeds of Cephalotaxus fortunei. Their structures were elucidated by combination of spectroscopic data analyses, time-dependent density functional theory (TDDFT) ECD calculation, and single-crystal X-ray diffraction. Cephalofortine B represents the first example of C-5 epi-cephalotaxine-type alkaloid. All isolated compounds were tested for cytotoxicities against HCT-116, A375, and SK-Mel-28 cell lines. Cephalofortine E showed moderate activity against HCT-116 cell line, with an IC50 value of 7.46 ± 0.77 µM.