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The widespread emergence of pyrethroid-resistant Anopheles gambiae has intensified the need to find new contact mosquitocides for indoor residual spraying and insecticide treated nets. With the goal of developing new species-selective and resistance-breaking acetylcholinesterase (AChE)-inhibiting mosquitocides, in this report we revisit the effects of carbamate substitution on aryl carbamates, and variation of the 1-alkyl group on pyrazol-4-yl methylcarbamates. Compared to aryl methylcarbamates, aryl dimethylcarbamates were found to have lower selectivity for An. gambiae AChE (AgAChE) over human AChE (hAChE), but improved tarsal contact toxicity to G3 strain An. gambiae. Molecular modeling studies suggest the lower species-selectivity of the aryl dimethylcarbamates can be attributed to a less flexible acyl pocket in AgAChE relative to hAChE. The improved tarsal contact toxicity of the aryl dimethylcarbamates relative to the corresponding methylcarbamates is attributed to a range of complementary phenomena. With respect to the pyrazol-4-yl methylcarbamates, the previously observed low An. gambiae-selectivity of compounds bearing α-branched 1-alkyl groups was improved by employing β- and γ-branched 1-alkyl groups. Compounds 22a (cyclopentylmethyl), 21a (cyclobutylmethyl), and 26a (3-methylbutyl) offer 250-fold, 120-fold, and 96-fold selectivity, respectively, for inhibition of AgAChE vs. hAChE. Molecular modeling studies suggests the high species-selectivity of these compounds can be attributed to the greater mobility of the W84 sidechain in the choline-binding site of AgAChE, compared to that of W86 in hAChE. Compound 26a has reasonable contact toxicity to G3 strain An. gambiae (LC50 = 269 μg/mL) and low cross-resistance to Akron strain (LC50 = 948 μg/mL), which bears the G119S resistance mutation.

XK469 is identified as a potent quinoxaline antineoplastic agent based on its significant clinical efficacy. It probably exerts its activity via DNA topoisomerase II (topo II) inhibition. To obtain more effective antineoplastic agents, a spectrum of peptidomimetic-type quinoxaline analogues of XK469 was herein designed, synthesized, and evaluated. Few compounds (e.g. 13a and 13b) exhibited obvious cytotoxicity indicated by in vitro anti-proliferative assay. SAR investigation revealed that introducing of hydrophobic tert-butylamine or dodecylamine moiety at the 3-position of quinoxaline core is favorable for achieving a better anti-proliferative potency, while peptidomimetic derivatives only yielded moderate cytotoxicity. Compounds with improved anti-proliferative activities also demonstrated decent anti-metastatic potencies comparable with that of doxorubicin (Doxo) based on in vivo mouse model study. The topo II-mediated kinetoplast DNA (kDNA) decatenation assay as well as molecular docking studies implicated that these compounds tend to be potent topo II inhibitors. Overall, compounds 13a and 13b, 13b in particular, standed out from various assessments and might be promising candidates for further chemical optimization.

New insecticides are needed for control of disease-vectoring mosquitoes and this research evaluates the activity of new carbamate acetylcholinesterase (AChE) inhibitors. Biochemical and toxicological characterization of carbamates based on the parent structure of terbam, 3-tert-butylphenyl methylcarbamate, was performed. In vitro enzyme inhibition selectivity (Anopheles gambiae versus human) was assessed by the Ellman assay, as well as the lethality to whole insects by the World Health Organization (WHO) paper contact assay. Bromination at the phenyl C6 position increased inhibitory potency to both AChEs, whereas a 6-iodo substituent led to loss of potency, and both halogenations caused a significant reduction of mosquitocidal activity. Similarly, installation of a hexyl substituent at C6 drastically reduced inhibition of AgAChE, but showed a smaller reduction in the inhibition of hAChE. A series of 4-carboxamido analogs of the parent compound gave reduced activity against AgAChE and generally showed more activity against hAChE than AgAChE. Replacement of the 3-t-buyl group with CF3 resulted in poor anticholinesterase activity, but this compound did have measurable mosquitocidal activity. A series of methyl- and fluoro- analogs of 3-trialkylsilyl compounds were also synthesized, but unfortunately resulted in disappointing activity. Finally, a series of sulfenylated proinsecticides showed poor paper contact toxicity, but one of them had topical activity against adult female Anopheles gambiae. Overall, the analogs prepared here contributed to a better understanding of carbamate structure&ndash, activity relationships (SAR), but no new significant leads were generated.

Eight 3-O-alkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin through two synthetic approaches. A one-pot reaction, starting with aerobic oxidation of silibinin followed by direct alkylation of the phenolic hydroxyl group in the subsequent 2,3-dehydrosilibinin, furnishes the desired derivatives in 11–16% yields. The three-step procedure employing benzyl ether to protect 7-OH in silibinin generates the desired derivatives in 30–46% overall yields. The antiproliferative activity of the 2,3-dehydrosilibinin derivatives against both androgen-sensitive and androgen-insensitive prostate cancer cells have been assessed using a WST-1 cell proliferation assay. All derivatives exhibited greater antiproliferative potency than silibinin, with 2,3-dehydrosilibinins each possessing a three- to five-carbon linear alkyl group to 3-OH (IC50 values in a range of 1.71 to 3.06 μM against PC-3 and LNCaP cells) as the optimal derivatives. The optimal potency was reached with three- to five-carbon alkyl groups. Our findings suggest that 3-O-propyl-2,3-dehydrosilibinin effectively inhibits the growth of PC-3 prostate cancer cells by arresting cell cycle in the G0/G1 phase, but not by activating PC-3 cell apoptosis.

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner–Wadsworth–Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure–activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles.

We have corrected (Tetrahedron 2013, 69, 5859–5866) the structures of diterpenoid alkaloids reported in the Journal of Natural Products 2012, 75, 1145–1159. Our follow-up experiments compel us to present further revisions and clarifications on the diterpenoid alkaloids: (1) The naturally occurring forms of carmichaelines B, C, and D in Shi's paper (Journal of Natural Products 2012, 75, 1145–1159) are neither quaternary ammonium hydroxides 2–4 nor the initially revised trifluoroacetates. They are indeed the vakognavine-type C20-diterpenoid alkaloids 11–13. (2) The samples' concentration is the critical factor to the signals' intensity for F3CCOO− in the alkaloid trifluoroacetates. Incorporation of TFA into the corresponding salts resulted in signals' enhancement due to the closeness of δ values (∼116 ppm, ∼159 ppm) of free TFA and those of F3CCOO−. After removal of free TFA, the carbon signals of CF3COO− could become weaker, but their chemical shifts remained almost unchanged. The possible reason might be the ionization of TFA in acetone. (3) The NMR data cannot distinguish TFA from trifluoroacetates (e.g., F3CCOONa and C19-diterpenoid alkaloid trifluoroacetates), indicating that the signal at around δ −76 cannot be used to exclude the existence of trifluoroacetates. In addition to the NMR and CSI-MS data, 1H–15N HMBC technique was also used to distinguish the free alkaloids from their trifluoroacetates. (4) The X-ray crystallographic analysis of compound 20 confirmed that the ‘new alkaloid’ (-b) in the Shi's paper is indeed the known compound aconifine trifluoroacetate. (5) Collectively, Shi's paper mixed-up the free alkaloids with their salts and the concepts of structure and conformation. Naming different structures with A-b and A-c is also confusing.

Zampanolide and its structural relative dactylolide are promising new tubulin-assembly agents with the potential to become new anticancer drugs. This review covers their sources and isolation, structures, anticancer potential, mechanism of action, and syntheses., Covering: through January 2014 Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure–activity studies, mechanism of action, and syntheses.

Two coordination polymers, [Co2(Hcpip)2(phth)]n·3n(H2O) (1) and [Mn2(Hcpip)2(phth)]n (2), {H2cpip = 2-(2-carboxyphenyl)imidazo[4,5-f](1,10)- phenanthroline, H2phth = phthalic acid}, were hydrothermally synthesized and characterized by elemental analysis, IR spectroscopy, and single-crystal X-ray diffraction. Complex 1 is a 1D chain, in which the dinuclear [Co2(Hcpip)2]2+ units are linked through (phth)2– anions. Complex 2 is a 2D layer structure, which is constructed from the 1D chains bridged by (phth)2– anions. The magnetic properties of 1 and 2 show that the weak ferromagnetic interactions occurred between CoII ions in 1 and a weak antiferromagnetic interactions exist between MnII ions in 2. These two complexes have good thermal stabilities.

Four novel lead(II) metal–organic coordination polymers, [Pb2(Hcpip)4]n (1), [Pb2(Hcpip)2(ox)]n (2), [Pb2(Hcpip)2(suc)]n (3), [Pb2(cpip)2(glu)(H2O)]n·n(H2O) (4) [H2cpip = 2-(2-carboxyphenyl)imidazo(4,5-f)(1,10)-phenanthroline, H2ox = oxalic acid, H2suc = succinic acid, H2glu = glutaric acid], have been hydrothermally synthesized and characterized by elemental analysis, IR, single crystal X-ray diffraction. Complex 1 exhibits a 2D layer structure. Complexes 2 and 3 feature 1D loop-and-chain structures, which are connected by strong π⋯π interaction to result in 2D layer structures. Complex 4 has the dinuclear parallelogram of [Pb2O2] and shows a 2D layer structure. The structural differences of these complexes give some insights into the effect of different auxiliary ligands on the construction of coordination polymers under the same hydrothermal conditions. The fluorescent properties of 1–4 were investigated.

Eleven C19-diterpenoid alkaloids reported in Shi's paper were isolated or synthesized. Their 13C NMR and DEPT spectra were recorded using (CD3)2CO+TFA as solvents. Comparison of the acquired NMR data with those reported in Shi's paper, in combination with the fact that all alkaloids, expect for 8, 27, and 28, reported in Shi's paper were isolated using TFA as part of solvent system, led to the following revisions of Shi's paper: (1) compounds 1–4, 6, 7a, 9–26 should be their respective trifluoroacetates. Their structures were revised as 1a–4a, 6a, 7a′, 9a–26a; (2) compounds 7, 27a, and 28a are trifluoroacetates of free bases 8, 27, and 28, respectively; compound 7 should be corrected as 7b; (3) ring A of free bases (such as 8, 27, and 28) exists as chair conformation; while ring A of the protonated versions (such as 7, 27a, 28a, 6a, 9a–26a) exists as boat conformation. Consequently, compounds 7 and 8 are apparently not a pair of conformational isomers, instead, they are indeed a free base and its protonated version existing as a trifluoroacetate, respectively; (4) ‘new’ compounds 6, 13, and 15 are the protonated versions 6a, 13a, and 15a, respectively, of the corresponding known alkaloids, aconifine, deoxyaconitine, 14-benzoylaconine. In addition, all 1H (13C) NMR data for the free bases of new compounds 8, 9, 10, 17, and 24 (Tables 3 and 4) were also assigned based on their 2D NMR spectra.

The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1α-OMe or 1α-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3α-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6α-OMe, 13-OH, 15α-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom.

Treatment of imines 5 and 7 , both prepared from the C 19 -diterpenoid alkaloid deltaline ( 1 ), with NaNO 2 –HCl resulted in the formation of diterpene 6 with an eight-membered ring through a sequence of denitrogenation and enlargement of ring B. In addition, two unusual skeletal rearrangements of diterpene 6 were also observed, leading to two structurally novel products 8 and 10 . The structures of compounds 8 and 10 were confirmed by their X-ray crystallographic analyses and 2D NMR data.

O-Demethylation at C-1 in the C19-diterpenoid alkaloids is very challenging. In this paper, it was firstly observed that 10-OH group in deltaline (1) is a determining factor for the O-demethylation reaction. After removal of this hydroxyl group, 1-O-methyl group in the corresponding deltaline analogs can be readily removed by treatment with HBr–HOAc. Meanwhile, the C-14 atom in bromides 18 or 20 can be extruded under basic condition probably via a sequence, including Grob fragmentation, aerobic oxidation, deformylation, and SN2 nucleophilic substitution, to give enone 21 (70%) and oxetane 22 (14%). The structure of compound 22 was confirmed by X-ray crystallographic analysis of its derivative 21.

The O-acyl group at C-1 of two C19-diterpenoid alkaloids 2 and 5 was transferred to the secondary amine nitrogen to form amides 3 and 6 in the basic condition. This kind of O-to-N intramolecular acyl migration could be caused by the near distance between the nucleophilic nitrogen atom and the carbonyl group of the ester at C-1 in the C19-diterpenoid alkaloids, which is consistent with the conformation of rings A and E in the C19-diterpenoid alkaloids.

Lactam 2, prepared from deltaline (1), is an analog of C19-diterpenoid alkaloid with a hydroxyl group at C-6 and a ketone carbonyl group at C-7. Treatment of this lactam with thionyl chloride or methanesulfonyl chloride, or reaction of this lactam under Chugaev condition led to an unusual rearrangement of its E/F ring system to yield a lactone 10 in a yield range of 43–74%. The structure of 10 was confirmed by its 2D NMR data and X-ray crystallographic analysis.

The first biomimetic conversion from the aconitine-type C(19)-diterpenoid alkaloids to the corresponding alkaloids of lactone-type C(19)-diterpenoid alkaloid has been achieved. Chasmanine was used as starting material with Baeyer-Villiger oxidation as a key reaction. It was also observed that the oxygenated group at C-16 did not change the relative migration tendencies of C-13 and C-9 during the oxidation. Meantime, a novel D-ring fragmented compound was obtained during the course of the present investigation. The plausible mechanism of the formation of this compound was also proposed.

A convergent and efficient formal synthesis of (±)-atisine has been accomplished. The synthetic strategy is to efficiently construct the bicyclo[2.2.2]octane ring moiety by an oxidative dearomatization/intramolecular Diels-Alder cycloaddition cascade. The first total synthesis of another atisine-type C(20)-diterpenoid alkaloid, (±)-isoazitine, has also been achieved employing the same strategy.

An tricyclic AEF fragment of C19-diterpenoid alkaloid bearing an angular methyl group and the oxygen function groups at C-1 and C-6 was successfully synthesized. The synthesis features a stereoselective intramolecular Diels–Alder reaction and a highly efficient intramolecular Mannich reaction as well as efficient functional groups transformations.

A concise strategy for construction of B/C/D ring system of C19-diterpenoid alkaloids was described, which features a highly diastereoselective intramolecular Diels–Alder reaction of masked o-benzoquinone and an efficient Wagner–Meerwein 1,2-shift rearrangement. The functional group transformations of rearrangement product 19 demonstrate a potential for stereoselective installation of oxygen functions on D-ring of many type of C19-diterpenoid alkaloids.

A selective intramolecular transacylation from C-4 to C-5 of taxoids, which occurred simultaneously with the oxetane D-ring opening and was promoted by TiCl4, was presented. The optimal condition was found to be treatment of substrates in double dose of dichloromethane (per mg of substrate dissolved in 2 mL DCM) with 1 eq of TiCl4 at 25°C for 10 min.

Two novel zinc(II) coordination polymers, [Zn2(Hcpip)2(ox)]n·2nH2O (1) and [Zn4(Hcpip)2(cpip)2(ox)]n·5nH2O (2), (H2cpip = 2-(2-carboxyphenyl) imidazo [4,5-f]1,10-phenanthroline, H2ox = oxalic acid), have been hydrothermally synthesized and characterized by elemental analysis, IR, single crystal X-ray diffraction. Compound 1 is a 1D chain, in which the dinuclear [Zn2(Hcpip)2]2+ units are linked through (ox)2− anions. Compound 2 is a 2D layer structure, which is constructed from the 1D chains bridged by (ox)2− anions. These two compounds possess strong luminescence and good thermal stabilities.

Four novel taxoid analogs were conversionally synthesized from the C(19)-diterpenoid alkaloid deltaline, and their cytotoxic activities were evaluated against a small panel of cancer cell lines.

An AE azabicyclic fragment, with a β-hydroxyl group at C-5 and a substituent at C-1, of the C 19 -diterpenoid alkaloids, was synthesized. The key reactions include an intramolecular Claisen-type condensation, double Mannich reaction, and stereoselective nucleophilic addition of carbonyl group with the assistance of steric effect of 1β-substituent.

Three new C20-diterpenoid alkaloids, along with twenty-two known alkaloids, were isolated from the whole herbs of Delphinium tatsienense. The new alkaloids include a vakognavine-type C20-diterpenoid alkaloid, designated as tatsienenseine A (1), and two hetisine-type C20-diterpenoid alkaloids, designated as tatsienenseines B (2) and C (3). Their structures were elucidated by IR, HR-ESI-MS, 1D- and 2D-NMR analyses.

Further investigation on the roots of Aconitum piepunense led to the isolation of a novel bis-diterpenoid alkaloid designated as piepunine (1). Its structure was established by extensive interpretation of its 1D- and 2D-NMR data, high-resolution ESI-MS, and IR spectra. Piepunine represents the first example of an atisine–denudatine-type bis-diterpenoid alkaloids.

Glycine-derived 1H-benzo[e][1,4]diazepin-2(3H)-ones (BZDs) 5d-g featuring C9- and N1- substitution exhibit enantiomerization barriers too high to be measured by (1)H NMR coalescence experiments. To address this problem, we found that room-temperature H/D exchange of these compounds is remarkably selective, affording only the axial-d(1) isotopomers. (1)H NMR spectroscopy was then employed to measure the rate of conformational inversion of these d(1)-compounds at elevated temperatures. These studies reveal the highest enantiomerization barriers (up to 28 kcal/mol) ever determined for a BZD. Density functional theory calculations match the experimental enantiomerization barriers within 1.2 kcal/mol.

Three new C19-diterpenoid alkaloids, giraldines A (1), B (3) and C (4), were isolated from the roots of Delphinium giraldii Diels, together with three known C19-diterpenoid alkaloids, dihydrogadesine (5), tatsiensine (6) and siwanine A (7), as well as their structures were elucidated by chemical evidence and spectral analyses, including m, MS, 1D NMR and 2D NMR.

Three new C(19)-diterpenoid alkaloids, umbrosumines A-C (1-3), and 11 known compounds (4-14) were isolated from the roots of Delphinium umbrosum. Their structures were elucidated on the basis of the spectroscopic data interpretation.

Trichocarpinine (1), the first hetidine–hetisine type bisditerpenoid alkaloid, was isolated from the whole herbs of Aconitum tanguticum var. trichocarpum. Its structure was determined by a combination of spectroscopic techniques, including HR-ESI-MS and 1D- and 2D-NMR experiments. Its plausible biogenetic pathway was proposed as well (Scheme).

Two novel C-nor-B-homo aconane-type diterpenes 4 and 5, featuring a unique eight-membered ring system, were obtained by the treatment of C-nor-C19-diterpenoid alkaloid 3 with HNO2 in 8% and 21% yields, respectively. Structures of these two compounds were established based on the combination of spectroscopic data, including HRESIMS, 1D and 2D NMR data. A plausible mechanism for the formation of 4 and 5 is also presented.

Three new C(19)-diterpenoid alkaloids, anthriscifoldines A-C (1-3), and two new C(18)-diterpenoid alkaloids, anthriscifolcines F and G (5, 6), were obtained from the whole herbs of Delphinium anthriscifolium var. savatieri during our further investigation on a larger scale of recollected plants. Their structures were elucidated based on the interpretation of NMR and high-resolution ESI-MS data, and chemical transformation. In addition, five known C(19)-diterpenoid alkaloids were also isolated and identified as nudicaulamine (4), delbruninol (7), blacknine (8), winkleriline (9), and deltaline (10).

For evaluation of C(18)- and C(19)-diterpenoid alkaloids as analgesics, three C(19)-diterpenoid alkaloids were isolated from the roots of Aconitum hemsleyanum var. circinatum and A. transsecutum; and twenty-five semisynthetic C(18)- or C(19)-diterpenoid alkaloids were prepared from lappaconitine, crassicauline A or yunaconitine. In a mice acetic acid-induced abdominal constriction assay, four crassicauline A analogs and three yunaconitine analogs exhibited good analgesic activities with 77.8-94.1% inhibition range in 0.1-10 mg/kg subcutaneous (s.c.) dose range at the point of 20 min after drug administration. Among them, 8-O-deacetyl-8-O-ethylcrassicauline A (ED(50)=0.0972 mg/kg) and 8-O-ethylyunaconitine (ED(50)=0.0591 mg/kg) were the most potent analgesics relative to the reference drugs lappaconitine (ED(50)=3.50 mg/kg) and crassicauline A (ED(50)=0.0480 mg/kg). Analgesic activity data of these C(18)- and C(19)-diterpenoid alkaloids indicate that a tertiary amine in ring A, an acetoxyl or an ethoxyl group at C-8, an aromatic ester at C-14, and the saturation state of the ring D are important structural features necessary to the analgesic activity of the C(19)-diterpenoid alkaloids.

From the whole herbs of Delphinium majus, three new C(19)-diterpenoid alkaloids, majusines A-C (1-3), and six new C(20)-diterpenoid alkaloids, majusimines A-D (4-7) and majusidine A and B (8 and 9), have been isolated, together with 15 known compounds. The structures of compounds 1-9 were elucidated by spectroscopic data interpretation.

A novel approach to the highly functionalized taxane ABC ring system through chemical conversion of the C19-diterpenoid alkaloid deltaline (1) was achieved in six steps (1→17) in 18% overall yield mainly by Grob fragmentation, fission of the Δ9(14) double bond, followed by aldol condensation, and Pelletier's cleavage process.

A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.

A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO 2 Me pharmacophore at the para -, meta - or ortho -position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent (3-F, 3-OMe, 3-OH, 3-OAc, 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target linear 1,2-diarylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction followed by oxidation of the respective 1-(methylthiophenyl)-2-phenylacetylene intermediate. In vitro COX-1/COX-2 isozyme inhibition structure–activity studies identified 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene ( 12d ) as a potent COX-2 inhibitor (IC 50 = 0.32 μM) with a high COX-2 selectivity index (SI > 320) comparable to the reference compound rofecoxib (COX-2 IC 50 = 0.50 μM; COX-2 SI > 200). A molecular modeling study where ( 12d ) was docked in the binding site of COX-2 showed that the MeSO 2 COX-2 pharmacophore was positioned in the vicinity of the secondary COX-2 binding site near Val 523 . The 1-(4-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene ( 11f , COX-1 IC 50 = 1.00 μM; COX-2 IC 50 = 0.06 μM; COX-2 SI = 16.7) and 1-(3-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene ( 12f , COX-1 IC 50 = 6.5 μM; COX-2 IC 50 = 0.05 μM; COX-2 SI = 130) regioisomers exhibited comparable COX-2 inhibition, and moderately lower selective COX-2 selectivity, relative to the reference drug celecoxib (COX-1 IC 50 = 33.1 μM; COX-2 IC 50 = 0.07 μM; COX-2 SI = 472). The most potent anti-inflammatory agent 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene ( 12d ) exhibited moderate oral anti-inflammatory activity (ED 50 = 129 mg/kg) at 3 h postdrug administration relative to the reference drug celecoxib (ED 50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. The structure–activity data acquired indicate that the acetylene moiety constitutes a suitable scaffold (template) to design novel acyclic 1,2-diarylacetylenes with selective COX-2, or dual COX-1/COX-2, inhibitory activities.

Following the report on the synthesis of the 7,17-seco compounds [Wang, F.P., Yang, J.S., Chen, Q.H., Yu, L. and Li, B.G. (2000), Chem. Pharm. Bull. 48, 1912-1916], further studies on the reaction optimization for cleavage of the C(7),C(17) bond led to the 7,17-seco norditerpenoid alkaloids (e.g. 4, 9) in nearly 90% yield.

Two methods for the synthesis of N,19-seco norditerpenoid alkaloids were developed. One method prepared new N,19-seco norditerpenoid alkaloids possessing an oxaziridine group from yunaconitine in five steps involving acetylation, imination, quaternization, formation of N,O-mixed ketal, and oxidation in 50% overall yield. Another method provided a series of novel N,19-seco norditerpenoid alkaloids bearing the oximino or nitro groups through oxidation of the imine N-oxides with HIO4 in moderate yields. Two novel aconane- type diterpenes were synthesized from an N,19-seco nitro compound and an imine N-oxide through Nef reaction and HIO4 oxidation, respectively, in moderate yields. q 2002 Elsevier Science Ltd. All rights reserved.

Treatment of 3-acetylyunaconitine 2 from yunaconitine 1 with NBS at 40°C for 12 h afforded the 3-acetylyunaconitine azomethine 3 (48%). Reaction of 3 with CH 3 I in MeOH at room temperature overnight gave the iminium salt 4 (100%). Unexpectedly, treatment of 4 with 5% NaOH in methanol at room temperature for 20 min produced the rearrangement alkaloid 5 (38%) besides other unidentified compounds. Acetylation of 5 with Ac 2 O/pyridine containing a small amount of TsOH gave its two derivatives 6 (28%) and 7 (56%). The structure of 5 was confirmed using 2D NMR spectra and single crystal X-ray analysis of its acetyl derivative 7 .

Treatment of 14-methylsulfonyl pseudaconine 3 with DMF-NaOH at 150 degreesC for 10 h afforded the desired C-nor and 12,13-seco norditerpenoid alkaloids 16 alpha -methoxyl ketone 7 (70%) and 16 beta -methoxyl ketone 8 (15%) as a pair of epimers. Reaction of 7 with Br-2-HOAc at room temperature for 1.5-2 h produced the phenols 9 (40%), 10 (10%) and 13 (29%). Whereas, treatment of 8 with Br-2-HOAc under same conditions as the case for 7 gave phenolic compound 9 (38%) besides the by-product alpha -bromoketone 14 (25%). (C) 2001 Elsevier Science Ltd. All rights reserved.

New access to the 7, 17-seco norditerpenoid alkaloids 9 (60%) from yunnaconitine (5), as well as 14 (46%) and 15 (22%) from isotalatizidine (10), via selective hydrolysis, chlorination and reduction with NaBH4 is described.

A novel diterpene with an unprecedented pentacyclic skeleton, designated as atropurpuran (1), featuring a unique motif to fuse two bicyclo[2.2.2]octane units, was isolated from the roots of Aconitum hemsleyanum var. atropurpureum. Its structure and relative configuration were established by NMR techniques and single-crystal X-ray diffraction. The biosynthetic origin of 1 was proposed to be Hetidane-type diterpenoid.

Further investigation of the roots of Delphinium giraldii DIELS led to the isolation of three new C(19)-diterpenoid alkaloids, giraldines G (1), H (2), and I (3). The structures of 1-3 were established based on spectroscopic evidence.

Three new norditerpenoid alkaloids, trifoliolasines A (1), B (3), and C (5), were isolated from the whole plant of Delphinium trifoliolatum FINET et GAGNEP, and their structures were established based on the spectral data.

Four new norditerpenoid alkaloids, leueantines A (1), B (2), C (3), and D (4), were isolated from the roots of Aconitum hemsleyanum var. leueanthus. The structures of 1-4 were established by spectroscopic evidence.

Intramolecular transacylation from C-4 to C-5 of taxoids in the presence of TiCl4 proceeds with concomitant oxetane D-ring opening to give novel taxoid derivatives, as demonstrated for paclitaxel (I).

The synthesis of a novel D-ring modified docetaxel analogue, in which the oxetane ring is replaced with a γ-lactone, was achieved from 10-deacetylbaccatin III. The key steps of the synthesis include the direct acetylation of the secondary hydroxyl group at C-5 and D-ring opening and intramolecular aldol reaction to form the γ-lactone. In MTT assays, this analogue proved to have equipotent cytotoxicity relative to paclitaxel towards HCT8, HePG2 and BGC23 cancer cell lines, and be more potent than paclitaxel against A549 and A375. It represents the first example of D-ring modified taxoids with significant cytotoxicity.

The conversional synthesis of taxoids by the BAC sequence from the C(19)-diterpenoid alkaloids, 14-acetyltalatisamine (1), yunaconitine (12), and 14-acetylchasmanine (19), was designed and explored. Two aconane-type diterpenes 17 and 28, the advanced intermediates for our conversional synthesis, were synthesized. The key steps include the rupture of the C(7)-C(17) bond, the formation of imine, and the denitrogenation.

Six new bisbenzylisoquinoline alkaloids, racemosidines A-C (1-3) and racemosinines A-C (4-6), and four known compounds were isolated from the roots of Cyclea racemosa. Compound 1 is the first bisbenzylisoquinoline alkaloid reported that has diphenyl ether bridges at C-11/C-7' and C-8/C-12' and a benzyl-phenyl ether bridge at C-7/C-11'. Structures and absolute configurations of 1-6 were established by interpretation of spectroscopic data and confirmed by X-ray crystallographic analysis of representative compounds. Compounds 1-3 exhibited significant cytotoxicity against HCT-8 and BEL-7402 tumor cells, and compound 1 was also cytotoxic against A2780 tumor cells.

A new and efficient approach toward the conversion of C19-diterpenoid alkaloids into diterpenes with [6+8+5+6] ring system is reported. Treatment of imines 5, 14, and 24 derived from the C19-diterpenoid alkaloids with NaNO2–NaOAc–HOAc afforded a series of novel rearrangement diterpenes 6—8, 15—19, and 25—27, respectively. The lactone 11 was obtained in 41% yield by treating 5 with NaNO2–HBr–Br2. The formation of diazonium intermediate is postulated, which was subsequently subjected to skeletal rearrangement, leading to the enlargement of B ring. All the new compounds were isolated and fully characterized.