Isolation, structure determination, and anti-cancer activity of apoptolidin D

The isolation, characterization, and preliminary biological activity of apoptolidin D, a new apoptolidin that exhibits anti-proliferative activity against H292 human lung carcinoma cells at nanomolar concentrations, are reported. Its equilibration with isoapoptolidin D and characterization of the latter are also described. [structure: see text].     

Toward a stable apoptolidin derivative: identification of isoapoptolidin and selective deglycosylation of apoptolidin

[formula: see text] Isoapoptolidin was isolated from crude fermentation extracts of the apoptolidin-producing microorganism Nocardiopsis sp. Apoptolidin isomerizes to isoapoptolidin upon treatment with methanolic triethylamine to establish a 1.4:1 equilibrium mixture of isoapoptolidin and apoptolidin. Semisynthesis of a peracetylated and deglycosylated derivative of apoptolidin is also described.     

Studies on the synthesis of apoptolidin: synthesis of a C1-C27 fragment of apoptolidin D

Synthesis of a C(1)-C(27) fragment, a key intermediate in the synthesis of apoptolidin D, is reported. The synthesis involves a combination of Heck coupling and Horner-Wadsworth-Emmons reaction for the C(1)-C(7) trienoate portion and an efficient Suzuki cross-coupling protocol for the C(10)-C(13) diene portion.     

Apoptolidinone A: synthesis of the apoptolidin A aglycone

An efficient stereocontrolled synthesis of apoptolidinone A, the aglycone of apoptolidin A is described. The synthetic strategy relies on a cross coupling between C11/C12 of a northern half (C1-C11) and a southern part (C12-C28) followed by a ring-size selective macrolactonization. Key steps for the introduction of the southern half stereocenters are a stereoselective aldol reaction, a substrate controlled dihydroxylation and a chelation-controlled Grignard/aldehyde addition. The conjugated triene of the northern half was built up successively by E-selective Wittig reactions. L-Malic acid was chosen as the chiral pool source for the C8/C9 stereocenters. The final cleavage of the silyl ethers and the conversion of the C21 methyl ketal into the hemiketal was achieved by HF.pyridine.     

Correlation of F0F1-ATPase inhibition and antiproliferative activity of apoptolidin analogues

[structure: see text] Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F(0)F(1)-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels-Alder adduct, were analyzed for antiproliferative activity in E1A-transformed rat fibroblasts. Potent F(0)F(1)-ATPase inhibition was not a sufficient determinant of antiproliferative activity for several analogues, suggesting the existence of a secondary biological target or more complex mode of action for apoptolidin.     

Total synthesis and antifungal activity of a carbohydrate ring-expanded pyranosyl nucleoside analogue of nikkomycin B

In a study aimed at investigating an as yet unknown structure-activity relationship of the nikkomycin family of antifungal peptidyl nucleoside antibiotics, the present research reports the synthesis and antifungal evaluation of a carbohydrate ring-expanded pyranosyl nucleoside analogue of nikkomycin B. Employing a convergent synthetic route, independent synthesis of the N-terminal amino acid side chain and a stereoselective de novo construction of the desired pyranosyl nucleoside amino acid fragment was followed by peptidic coupling of the two components, leading to the first synthesis of a carbohydrate ring-enlarged pyranosyl nikkomycin B analogue. In vitro biological evaluation of the above analogue against a variety of human pathogenic fungi demonstrated significant antifungal activity against several fungal strains of clinical significance.     

Noteworthy observations accompanying synthesis of the apoptolidin disaccharide

A stereoselective synthesis of the apoptolidin disaccharide is reported. The key chemistry features a new transformation utilizing a highly selective tetramethylalkoxyalanate[v]-directed syn-methylation of a vinylogous ester, isolation of a hydrate of a 2-keto sugar, an eco-friendly radical cleavage of a bromomethyl group, and an efficient preparation of a fluorodisaccharide via the use of XtalFluor-E.     

Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation

The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.     

Total synthesis of apoptolidin: construction of enantiomerically pure fragments

A general strategy for the total synthesis of the antitumor agent apoptolidin (1) is proposed, and the chemical synthesis of the defined key building blocks (4, 5, 6, 8, and 9) in their enantiomerically pure forms is described. The projected total synthesis calls for a dithiane coupling reaction to construct the C(20)-C(21) bond, a Stille coupling reaction to form the C(11)-C(12) bond, and a Yamaguchi macrolactonization to assemble the macrolide ring, as well as two glycosidation reactions to fuse the carbohydrate units onto the molecule. First and second generation syntheses to the required fragments for apoptolidin (1) are described.     

Development of an end-game strategy towards apoptolidin: a sequential Suzuki coupling approach

An end-game strategy towards the synthesis of apoptolidin has been demonstrated in a model study, in which the C(1)-C(15) fragment was successfully assembled using three consecutive Suzuki coupling reactions.     

Toward a structure-activity relationship for apoptolidin: selective functionalization of the hydroxyl group array

[reaction: see text] To investigate the structural basis for the exceptional selectivity and activity of apoptolidin (1), a strategy has been devised that allows for selective functionalization of seven of its eight hydroxyl groups based on progressive silyl protection, derivatization, and deprotection. The syntheses of these derivatives and their ability to inhibit F(0)F(1)-ATPase are reported.     

Enantioselective preparation of the C1-C11 fragment of apoptolidin

[reaction: see text] A novel approach toward the synthesis of the triene portion of the biologically active polyketide apoptolidin is described. The use of an iterative thionyl chloride rearrangement/oxidation sequence to construct trisubstituted olefins is explored.     

Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues

Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.     

Facile synthetic access to and biological evaluation of the macrocyclic core of apoptolidin

Oxidative cleavage of the C-20/C-21 bond in apoptolidin (1) provides two fragments of similar complexity, facilitating a divide-and-diversify strategy for the determination of the structural basis for apoptolidin's biological activity, the remarkably selective induction of apoptosis in sensitive cell lines. The ability of compounds derived from this cleavage to inhibit mitochondrial F(0)F(1)-ATPase is reported. [structure: see text]     

季戊四醇单侧修饰的Anderson型铬钼酸盐烷氧衍生物异构体的合成与晶体结构

在加热条件下,发现氯化铵可以使季戊四醇单侧修饰的Anderson型铬钼酸盐发生结构变异,Anderson型多酸母体上的季戊四醇配体由正中心位置异构到非正中心位置(季戊四醇配体的一个烷氧基从取代多酸骨架中的μ_3-O桥氧原子异构为取代骨架中的μ_2-O桥氧原子),得到其χ同分异构体(NH_4)_3{χ-[Cr(OH)_3Mo_6O_(18)(OCH_2)_3CCH_2OH]},并通过电喷雾质谱ESI、红外光谱IR和单晶X射线衍射的方法确定了该化合物的结构.晶体测定及分析结果表明,该化合物属单斜晶系,P2_1/n空间群,晶胞参数a=1.053 68(4)nm,b=2.911 72(6)nm,c=1.124 70(7)nm,α=90°,β=117.45(6)°,γ=90°,Z=4,V=3.062 1(3)nm~3.     

Synthesis of diastereomeric,deoxy and ring-expanded sulfone analogues of aigialomycin D

Several analogues of the fungal natural product aigialomycin D (AmD) have been synthesised. These include the stereoisomer 5′R,6′S-AmD, 2,4-di-deoxyAmD, 1′,2′,7′,8′-tetrahydroAmD and a 15-membered macrocyclic sulfone. Growth inhibitory activities of these compounds against the HL-60 leukaemic cell line were measured. The ring-expanded sulfone and tetrahydro-analogue were found to have similar IC₅₀ values to the natural product, whereas the 5′R,6′S-stereoisomer was inactive. Energy minimisation of AmD and the synthesised analogues resulted in a range of lowest energy conformers, from planar, open arrangements of the macrocycle in AmD and tetrahydroAmD to bent, L-shaped structures for the sulfone. The synthesis of methyl orsellinate was investigated and optimised as part of this work. A stereodivergent route to both enantiomers of the diol fragment from d-ribose was also achieved.     

Executing and rationalizing the synthesis of a difluorinated analogue of a ring-expanded calystegine B2

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.     

Studies on the synthesis of apoptolidin A. 2. Synthesis of the disaccharide unit

Disaccharide 3 correspoinding to the disaccharide unit of apoptolidin A has been synthesized via the regio- and stereoselective TBS-OTf-promoted beta-glycosidation reaction of 2,6-dideoxy-2-iodo-beta-glucopyranosyl acetate (5) and p-methoxybenzyl 2,6-dideoxy-2-iodo-3-C-methyl-alpha-mannopyranoside (11).     

A divergent approach to apoptolidin and FD-891: asymmetric preparation of a common intermediate

Biologically active Apoptolidin and FD-891 have structural similarity in their macrocyclic cores. Asymmetric preparation of a common intermediate in the total synthesis of these two macrolides is presented. A modified Masuyama Sn-allylation was employed to control the relative stereochemistry in the synthesis of the intermediate.