Natural Products Chemistry Breaking News

Five novel tigliane-type diterpenes, stelleracins A–E (3–7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from the roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3–5 showed potent anti-HIV activity (EC90 0.00056–0.0068 μM) and relatively low or no cytotoxicity (IC50 4.4–17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates.

Yoshihisa Asada*†, Aya Sukemori‡, Takashi Watanabe§, Kuber J. Malla, Takafumi Yoshikawa‡, Wei Li*, Xinzhu Kuang, Kazuo Koike, Chin-Ho Chen, Toshiyuki Akiyama#, Keduo Qian#, Kyoko Nakagawa-Goto#, Susan L. Morris-Natschke#, Yan Lu#, and Kuo-Hsiung Lee

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300815t

Publication Date (Web): April 23, 2013

A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.

Jhih-Bin Chen†, Ting-Rong Chern‡, Tzu-Tang Wei§, Ching-Chow Chen§, Jung-Hsin Lin*‡#, and Jim-Min Fang

J. Med. Chem., Article ASAP

DOI: 10.1021/jm400179b

Fumiquinazoline L (1), an alkaloid with a heptacyclic skeleton formed via a bridging hemiaminal linkage, was isolated from a gorgonian-derived Scopulariopsis sp. fungus. The structure and absolute configuration of the new compound were identified by comprehensive spectroscopic data and X-ray diffraction analysis. During acid hydrolysis of 1, the isomerization of the valine residue was observed and also studied in different conditions. Fumiquinazoline L (1) showed no cytotoxic or antibacterial activities.

Chang-Lun Shao†, Ru-Fang Xu†, Mei-Yan Wei†‡, Zhi-Gang She*§, and Chang-Yun Wang

J. Nat. Prod., Article ASAP

DOI: 10.1021/np4002042

Publication Date (Web): April 15, 2013

Sacchathridine A (1) was isolated from the fermentation broth of strain Saccharothrix sp. MI559-46F5. The structure was determined as a new naphthoquinone derivative with an acetylhydrazino moiety by a combination of NMR, MS spectral analyses, and chemical degradation. Compound 1 showed inhibitory activity of prostaglandin E2 release in a concentration-dependent manner from human synovial sarcoma cells, SW982, with an IC50 value of 1.0 μM, but had no effect on cell growth up to 30 μM.

Koichi Nakae*, Ikuko Kurata, Fukiko Kojima, Masayuki Igarashi, Masaki Hatano, Ryuichi Sawa, Yumiko Kubota, Hayamitsu Adachi, and Akio Nomoto

J. Nat. Prod., Article ASAP

DOI: 10.1021/np3006327

Publication Date (Web): April 12, 2013

Graphiopsis chlorocephala was separated from the surface-sterilized healthy leaves of Paeonia lactiflora (Paeoniaceae) and cultivated with nicotinamide (an NAD+-dependent HDAC inhibitor). The culture conditions significantly enhanced secondary metabolite production in the fungus and led to the isolation of a structurally diverse set of new benzophenones, cephalanones A–F (1–6), and a known 2-(2,6-dihydroxy-4-methylbenzoyl)-6-hydroxybenzoic acid (7). The structures of 1–6 were determined from NMR data, single crystal X-ray diffraction, and chemical transformations.

Teigo Asai*†, Sae Otsuki†, Hiroaki Sakurai‡, Kouwa Yamashita§, Tomoji Ozeki‡, and Yoshiteru Oshima

Org. Lett., Article ASAP

DOI: 10.1021/ol400781b

Publication Date (Web): April 11, 2013

Three new alkaloids, hyrtimomines A–C (1–3), were isolated from an Okinawan marine sponge Hyrtios sp. The structures of 1–3 were elucidated on the basis of spectroscopic analysis and application of a phenylglycine methyl ester (PGME) method. Hyrtimomines A (1) and B (2) are heteroaromatic alkaloids possessing a fused hexacyclic 6/5/6/6/7/5 ring system, while hyrtimomine C (3) is an alkaloid consisting of hydroxyindole and azepino-hydroxyindole moieties. Hyrtimomine A (1) exhibited cytotoxicity against KB and L1210 cells.

Rei Momose†, Naonobu Tanaka†, Jane Fromont‡, and Jun’ichi Kobayashi*†

A new chloro-trinoreremophilane sesquiterpene 1, three new chlorinated eremophilane sesquiterpenes 2–4, together with a known compound, eremofortine C (5), were isolated from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Structures were established using IR, HRMS, 1D and 2D NMR techniques. In addition, the plausible metabolic network of these isolated products is proposed. Compound 1 showed moderate cytotoxic activity against HL-60 and A549 cancer cell lines.

Mar. Drugs 2013, 11(4), 1399-1408; doi:10.3390/md11041399

Chemical investigation of the seeds of Croton tiglium afforded eight new phorbol diesters (three phorbol diesters, 1–3, and five 4-deoxy-4α-phorbol diesters, 4–8), together with 11 known phorbol diesters (nine phorbol diesters, 9–17, and two 4-deoxy-4α-phorbol diesters, 18 and 19). The structures of compounds 1–8 were determined by spectroscopic data information and chemical degradation experiments. The cytotoxic activities of the phorbol diesters were evaluated against the SNU387 hepatic tumor cell line, and compound 3 exhibited the most potent activity (IC50 1.2 μM).

Xiao-Long Zhang†§, Lun Wang†§, Fu Li†, Kai Yu‡, and Ming-Kui Wang

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300832n

The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety.

Patricia M. Flatt, Xiumei Wu, Steven Perry, and Taifo Mahmud*

J. Nat. Prod., Article ASAP

DOI: 10.1021/np400159aPublication Date (Web): April 22, 2013

Five new xanthoquinodins, A4–A6 (1–3), B4 (4), and B5 (5), were isolated from the crude extract of the endolichenic fungal strain Chaetomium elatum (No. 63-10-3-1), along with three known xanthoquinodins, A1–A3 (6–8). Their structures were determined by detailed spectroscopic analysis and comparison of the NMR data with those of the closely related compounds previously reported. The absolute configuration of 1 was established by X-ray crystallographic analysis and ECD calculation. The cytotoxic activity of all compounds was tested against HL-60, SMMC-7721, A-549, MCF-7, and SW480 human cancer cell lines. 

Guo-Dong Chen†, Ying Chen†, Hao Gao*†, Li-Qing Shen†, Yang Wu†, Xiao-Xia Li†, Yan Li‡, Liang-Dong Guo§, Ying-Zhou Cen, and Xin-Sheng Yao

J. Nat. Prod., Article ASAP

DOI: 10.1021/np400041y

Publication Date (Web): April 15, 2013

Two new alkaloids, polycarpathiamines A and B (1 and 2), were isolated from the ascidian Polycarpa aurata. Their structures were unambiguously determined by 1D, 2D NMR, and HRESIMS measurements and further confirmed by comparison with a closely related analogue, 3-dimethylamino-5-benzoyl-1,2,4-thiadiazole (4), that was prepared by chemical synthesis. Compounds 1 and 2 both feature an uncommon 1,2,4-thiadiazole ring whose biosynthetic origin is proposed. Compound 1 showed significant cytotoxic activity against L5178Y murine lymphoma cells (IC50 0.41 μM).

Cong-Dat Pham†, Horst Weber‡, Rudolf Hartmann§, Victor Wray, Wenhan Lin, Daowan Lai*†, and Peter Proksch

Org. Lett., Article ASAP

DOI: 10.1021/ol400791n

Publication Date (Web): April 12, 2013

As of early 2013, over 200 natural products are known to contain a nitrogen–nitrogen (N–N) bond. This report categorizes these compounds by structural class and details their isolation and biological activity.

Lachlan M. Blair and Jonathan Sperry

J. Nat. Prod., Article ASAP

DOI: 10.1021/np400124nPublication Date (Web): April 11, 2013

While numerous natural products (NPs) possess activity on central nervous system (CNS) targets, there has been no analytical approach to effectively identify compounds with high brain penetration potential in complex mixtures at the early stage of drug discovery. To overcome this issue, the performance of an in vitro parallel artificial membrane permeability assay for the blood–brain barrier (PAMPA-BBB) for natural products and for plant extracts has been validated and characterized. It was found that the PAMPA-BBB assay preserves its predictive power in the case of natural products and provides high phytochemical selectivity, which enables its use as a unique filtering tool in terms of selecting brain-penetrable compounds from plant extracts. Moreover, the present study has demonstrated that simple modifications in the assay design allow the direct use of PAMPA-BBB filtered samples in a dereplication process, as performed by NMR and LC-MS. The applicability of this procedure was demonstrated using extracts prepared from Tanacetum parthenium, Vinca major, Salvia officinalis, and Corydalis cava, representing different types of chemical diversity and complexity. Thus, the proposed protocol represents a potentially valuable strategy in the NP-based CNS drug discovery environment with a high-throughput screening platform.

Árpád Könczöl†, Judit Müller†‡, Emília Földes‡, Zoltán Béni§, Krisztina Végh, Ágnes Kéry, and György T. Balogh

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300882f

Publication Date (Web): April 8, 2013

Two novel reddish-orange alkaloids, mycoleptodiscin A (1) and mycoleptodiscin B (2), were isolated from liquid cultures of the endophytic fungus Mycoleptodiscus sp. that had been isolated from Desmotes incomparabilis in Panama. Elucidation of their structures was accomplished using 1D and 2D NMR spectroscopy in combination with IR spectroscopic and MS data. These compounds are indole-terpenes with a new skeleton uncommon in nature. Mycoleptodiscin B (2) was active in inhibiting the growth of cancer cell lines with IC50 values in the range 0.60–0.78 μM.

Humberto E. Ortega†, Paul R. Graupner‡, Yumi Asai§, Karen TenDyke, Dayong Qiu, Young Yongchun Shen, Nivia Rios, A. Elizabeth ArnoldΔ, Phyllis D. ColeyO#, Thomas A. KursarO#, William H. Gerwick□, and Luis Cubilla-Rios

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300792tPublication Date (Web): April 5, 2013