Microbial transformations of natural antitumor agents. 23. conversion of withaferin-A to 12β- and 15β-hydroxy derivatives of withaferin-A.

Fuska, J.; Prousek, Josef; Rosazza, John P. N.; Budêšínský, Miloś

doi:10.1016/0039-128x(82)90030-7

Cited by 24 publications

(23 citation statements)

References 14 publications

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“…The obvious differences between 2 and 1 were the presence of a 27-methyl carbon [ 13 C: δ 12.7; 1 H: 1.85 (3H, s)] in 2 and an oxygenated methylene 13 C: δ 56.7;1 H: δ 4.28 (1H,d,J = 12.5 Hz),4.23 (1H,d,J = 12.5 Hz)] in 1, suggesting that 2 is a 27-deoxy derivative of 1. This observation was supported by the 13 , by the NMR data comparison of the side chain moiety of 2 to those of 27-deoxywithanolides, 14,15 and by HMBC correlations of H 3 -27/C-24, C-25, and C-26. Acetylation of 2 with acetic anhydride in pyridine yielded the 4,19-diacetate (2a) and the 4-monoacetate (2b) (Tables 1 and 2), which confirmed the presence of hydroxy groups at C-4 and C-19 by a high-frequency shift of H-4 (from δ 3.63 in 2 to δ 4.79 in 2a and to δ 4.74 in 2b) and H 2 -19 (from δ 3.77, 4.32 in 2 to δ 4.32, 5.07 in 2a).…”

Section: Journal Of Natural Productssupporting

confidence: 52%

“…Compound 14 was assigned a molecular formula of C 33 H 48 O 10 by HRESIMS and NMR experiments and as an isomer of withalongolide M (13). The NMR data of these two compounds (Tables 4 and 5) were similar to each other, having the same functional groups and the same multiplicities for all other carbons present.…”

Section: Journal Of Natural Productsmentioning

confidence: 73%

“…a For cell lines used, see text. Withanolides 6,[9][10][11][12][13][14]17,18,20,and 21 were inactive for all cell lines used (IC 50 > 10 μM). …”

Section: ■ Experimental Sectionmentioning

confidence: 92%

“…The NMR data of its aglycon were similar to those of 1,6,27-trihydroxy-19-norwitha-1,3,5(10),24-tetraenolide (a 19-norwithanolide with an aromatic ring A). 21 A trisubstituted aromatic ring A in 11 was observed from the 1 H NMR (H-2: δ 7.14, 1H, d, J = 7.7 Hz; H-3: δ 7.34, 1H, t, J = 7.7 Hz; and H-4: δ 7.87, 1H, d, J = 7.7 Hz) and 13 …”

Section: Journal Of Natural Productsmentioning

confidence: 99%

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Cytotoxic withanolide constituents of Physalis longifolia

Zhang¹,

Samadi²,

Gallagher³

et al. 2012

Planta Med

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Fourteen new withanolides, 1−14, named withalongolides A−N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15−22). The structures of compounds 1−14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC 50 values in the range between 0.067 and 9.3 μM.C lassically defined withanolides are a group of C 28 ergostane-type steroids with a C-22,26 δ-lactone group, first isolated from the genus Withania. 1 They are present primarily in the Solanaceae family, which includes the genera Acnistus, Datura, Dunalia, Jaborosa, Nicandra, Physalis, Withanolides have attracted interest in recent years mainly due to their exhibition of significant biological activities, inclusive of antimicrobial, antitumor, anti-inflammatory, immunomodulatory, and insect-antifeedant activities. 2,3,6 It has been reported that those withanolides displaying the most promising antitumor characteristics contain an α,β-unsaturated ketone in ring A, a 5β,6β-epoxy group in ring B, and a nine-carbon side chain with an α,β-unsaturated δ-lactone group. 10 The typical withanolide withaferin A (16) (Figure 1) contains these three moieties and has been shown in vitro and in vivo to suppress the growth of an array of tumor cells, including breast, pancreatic, prostate, lung, leukemia, and head and neck squamous cell carcinoma (HNSCC), by inducing apoptosis, 11 thus possessing potential application as an antiproliferative agent. As part of an ongoing study of withanolides from plant sources, 11,12 a library of 224 native plant extracts from the U.S. Great Plains was evaluated for cytotoxic activities against HNSCC and melanoma cell lines using the MTS viability assay. One of the most promising leads, Physalis longifolia Nutt. (Solanaceae), commonly known as "long leaf groundcherry", was subjected to a phytochemical investigation, and the results are presented herein, including the details of the isolation and structure elucidation of 14 new withanolides (1−14), four acetylated derivatives (1a, 1b, 2a, and 2b), and eight known compounds (15−22). Their cytotoxicity was determined against HNSCC (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells. This constitutes the first report of a phytochemical and bioactivity study of P. longifolia. ■ RESULTS AND DISCUSSIONThe CH 2 Cl 2 −MeOH (1:1) extract of the aerial parts of the title plant and the EtOAc-soluble and n-BuOH-soluble fractions showed cytotoxicity against the above-mentioned cells with IC 50 values in the range between 0.7 and 9.8 μg/mL using a MTS assay. All ...

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Section: Journal Of Natural Productssupporting

confidence: 52%

Section: Journal Of Natural Productsmentioning

confidence: 73%

“…a For cell lines used, see text. Withanolides 6,[9][10][11][12][13][14]17,18,20,and 21 were inactive for all cell lines used (IC 50 > 10 μM). …”

Section: ■ Experimental Sectionmentioning

confidence: 92%

Section: Journal Of Natural Productsmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxic withanolide constituents of Physalis longifolia

Zhang¹,

Samadi²,

Gallagher³

et al. 2012

Planta Med

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“…Significant chemical transformations of WA ( 1 ) have involved (i) conversion of the 2(3)-en-1-one to a 1-one functionality; (ii) preparation of 3-substituted 2,3-dihydro analogues by Michael addition of nucleophiles (e.g., azide and alkyl/aryl thiols); , (iii) preparation of spiro-pyrrolizidine-indole adducts across the 2,3-double bond; (iv) derivatization of 4β-OH and/or 27-OH groups to their corresponding acetates and silyl ethers; (v) oxidation of the 4β-OH to a 4-oxo group followed by reduction leading to the 4α-OH analogue and its derivatization to the acetate; (vi) conversion of the 5β,6β-epoxy moiety into its corresponding 1,4-oxathiane analogues, thiiranes, amino alcohols, and alcohols; and (vii) substitution of the 27-OH group by an azido group . When subjected to microbial biotransformation using the fungus Cunninghamella echinulata , 1 afforded its 12β-hydroxy ( 3 ) and 15β-hydroxy ( 4 ) analogues, , which have been converted to their corresponding acetates …”

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confidence: 99%

Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation

et al. 2018

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Withanolides constitute a valuable class of bioactive natural products because some members of the class are known to exhibit cytotoxic activity and also induce a cytoprotective heat-shock response. In order to understand the relationship between their structures and these dual bioactivities of the withanolide scaffold, we obtained 25 analogues of withaferin A (WA) and withanolide D (WD) including 17 new compounds by semisynthesis involving chemical and microbial transformations. Hitherto unknown 16β-hydroxy analogues of WA and WD were prepared by their reaction with triphenylphosphine/iodine, providing unexpected 5β-hydroxy-6α-iodo analogues (iodohydrins) followed by microbial biotransformation with Cunninghamella echinulata and base-catalyzed cyclization of the resulting 16β-hydroxy iodohydrins. Evaluation of these 25 withanolide analogues for their cytotoxicity and heat-shock-inducing activity (HSA) confirmed the known structure-activity relationships for WA-type withanolides and revealed that WD analogues were less active in both assays compared to their corresponding WA analogues. The 5β,6β-epoxide moiety of withanolides contributed to their cytotoxicity but not HSA. Introduction of a 16β-OAc group to 4,27-di- O-acetyl-WA enhanced cytotoxicity and decreased HSA, whereas introduction of the same group to 4- O-acetyl-WD decreased both activities.

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Microbial Models for Drug Metabolism

Azerad

1999

Advances in Biochemical Engineering/Biotechnology

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Microbial transformations of natural antitumor agents. 23. conversion of withaferin-A to 12β- and 15β-hydroxy derivatives of withaferin-A.

Cited by 24 publications

References 14 publications

Cytotoxic withanolide constituents of Physalis longifolia

Cytotoxic withanolide constituents of Physalis longifolia

Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation

Microbial Models for Drug Metabolism

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