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Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric,Epimeric, and N‐Demethylated Analogues 下载免费PDF全文
Dr. Motoki Murai Takuya Kaji Dr. Takefumi Kuranaga Dr. Hiroshi Hamamoto Prof. Dr. Kazuhisa Sekimizu Prof. Dr. Masayuki Inoue 《Angewandte Chemie (International ed. in English)》2015,54(5):1556-1560
Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action. 相似文献
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Dr. Yu‐Peng He Hao Tan Dr. Lars Arve Dr. Sascha Baumann Prof. Dr. Herbert Waldmann Dr. Hans‐Dieter Arndt 《化学:亚洲杂志》2011,6(6):1546-1556
A full account on the synthesis of the antibiotic natural product biphenomycin B and several derivatives is reported, which employs a Suzuki coupling reaction of a free carboxylic acid and macrolactam formation as key transformations. Liberal exchange of the central amino acid was demonstrated. This procedure gave derivatives to study the influence of the polar side chain of the central amino acids on translation inhibition. 相似文献
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Hiroaki Itoh Kensuke Miura Koichi Kamiya Tomoya Yamashita Masayuki Inoue 《Angewandte Chemie (International ed. in English)》2020,59(11):4564-4571
We report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B ( 1 ), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin). 相似文献
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Koichi Kamiya Kensuke Miura Dr. Hiroaki Itoh Prof. Dr. Masayuki Inoue 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(3):1088-1093
Yaku′amide B ( 1 ) inhibits cancer cell growth through a unique mechanism of action. Compound 1 binds to mitochondrial FoF1-ATP synthase, inhibits ATP production, and enhances ATP hydrolysis. The presence of one (E)- and two (Z)-α,β-dehydroisoleucines (ΔIle) in the linear 13-mer sequence is the most unusual structural feature of 1 . To uncover the biological importance of these residues, we synthesized 1 and its seven E/Z isomers 2 – 8 by devising a new divergent solid-phase strategy. Both the (E)- and (Z)-ΔIle residues were stereoselectively constructed by traceless Staudinger ligation on resin to ultimately deliver 1 – 8 . All isomers 2 – 8 displayed effects on the inhibition of cell growth and ATP production, and enhanced ATP hydrolysis, thus indicating that 2 – 8 share the same mode of action as 1 . The least potent isomer, 8 , was isomeric at three ΔIle residues of the most potent 1 . These findings together indicate that the E/Z stereochemistry of the three ΔIle residues controls the magnitude of the biological functions of 1 . 相似文献
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Synthesis,Structural Reassignment,and Antibacterial Evaluation of 2,18‐Seco‐Lankacidinol B 下载免费PDF全文
Dr. Yanmin Yao Dr. Lingchao Cai Prof. Ian B. Seiple 《Angewandte Chemie (International ed. in English)》2018,57(41):13551-13554
Lankacidins are a group of polyketide natural products with activity against several strains of Gram‐positive bacteria. We developed a route to stereochemically diverse variants of 2,18‐seco‐lankacidinol B and found that the stereochemical assignment at C4 requires revision. This has interesting implications for the biosynthesis of natural products of the lankacidin class, all of which possessed uniform stereochemistry prior to this finding. We have evaluated 2,18‐seco‐lankacidinol B and three stereochemical derivatives against a panel of pathogenic Gram‐positive and Gram‐negative bacteria. 相似文献
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Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A 下载免费PDF全文
Hiromu Hattori Joel Roesslein Dr. Patrick Caspers Dr. Katja Zerbe Dr. Hideki Miyatake‐Ondozabal Dr. Daniel Ritz Dr. Georg Rueedi Prof. Dr. Karl Gademann 《Angewandte Chemie (International ed. in English)》2018,57(34):11020-11024
The macrocyclic antibiotic mangrolide A has been described to exhibit potent activity against a number of clinically important Gram‐negative pathogens. Reported is the first enantioselective total synthesis of mangrolide A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two β‐selective glycosylations. The synthesis of mangrolide A and its analogues enabled the re‐examination of its activity against bacterial pathogens, and only minimal activity was observed. 相似文献
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Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure–Activity Relationships 下载免费PDF全文
Dr. Silvia A. Albu Dr. Kalinka Koteva Dr. Andrew M. King Salma Al‐Karmi Prof. Gerard D. Wright Prof. Alfredo Capretta 《Angewandte Chemie (International ed. in English)》2016,55(42):13259-13262
The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo‐β‐lactamases NDM‐1 and VIM‐2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM‐1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9. 相似文献
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Dipl.‐Chem. K. Philip Wojtas Dr. Matthias Riedrich Dr. Jin‐Yong Lu Dr. Philipp Winter M. Sc. Thomas Winkler M. Sc. Sophia Walter Prof. Dr. Hans‐Dieter Arndt 《Angewandte Chemie (International ed. in English)》2016,55(33):9772-9776
Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3‐hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity. 相似文献
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Prof. Dr. K. C. Nicolaou Dr. Lei Shi Dr. Min Lu Dr. Manas R. Pattanayak Dr. Akshay A. Shah Dr. Heraklidia A. Ioannidou Dr. Manjunath Lamani 《Angewandte Chemie (International ed. in English)》2014,53(41):10970-10974
The total synthesis of cytotoxic polyketides myceliothermophins E ( 1 ), C ( 2 ), and D ( 3 ) through a cascade‐based cyclization to form the trans‐fused decalin system is described. The convergent synthesis delivered all three natural products through late‐stage divergence and facilitated unambiguous C21 structural assignments for 2 and 3 through X‐ray crystallographic analysis, which revealed an interesting dimeric structure between its enantiomeric forms. 相似文献
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Dr. Kei Kitamura Yoshihiko Maezawa Dr. Yoshio Ando Prof. Dr. Takenori Kusumi Prof. Dr. Takashi Matsumoto Prof. Dr. Keisuke Suzuki 《Angewandte Chemie (International ed. in English)》2014,53(5):1262-1265
A concise, highly convergent total synthesis of saptomycin B, a member of the pluramycin class of antitumor antibiotics, is reported. The target compound was assembled from four building blocks (a tricyclic platform, two sugars, and an alkynal) in 15% yield through 10 synthetic operations. The key steps included the regioselective installation of two amino sugars (L ‐vancosamine and D ‐angolosamine) on the tricycle and the efficient construction of the tetracyclic skeleton by an aldol reaction followed by formation of the pyranone. The unknown configuration at C14 was assigned as R. 相似文献
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Iraj Behroz Leonardo Kleebauer Kay Hommernick Maria Seidel Dr. Stefan Grätz Dr. Andi Mainz Dr. John B. Weston Prof. Dr. Roderich D. Süssmuth 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(35):9077-9086
The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N-terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para-coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin-based drug. 相似文献
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Dr. Hui Liu Dr. Yuqing Liu Zhuo Wang Dr. Xiangyou Xing Prof. Dr. Anita R. Maguire Prof. Dr. Hendrik Luesch Prof. Dr. Hui Zhang Prof. Dr. Zhengshuang Xu Prof. Dr. Tao Ye 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(21):6774-6784
Herein, we describe in full our investigations into the synthesis of grassypeptolide A ( 1 ) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late‐stage introduction of sensitive bis(thiazoline) heterocycles and 31‐membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly inhibited cancer cell proliferation in a dose‐dependent manner. It induced cancer cell apoptosis, which was associated with increased cleavage of poly(ADP‐ribose) polymerase (PARP) and decreased expression of bcl‐2 and bcl‐xL. Furthermore, grassypeptolide A also caused cell cycle redistribution by increasing cells in the G1 phase and decreasing cells in the S and G2 phases. In addition, cell cycle arrest was correlated with downregulation of cyclin D and upregulation of p27 and p21. 相似文献
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Dr. Masahito Yoshida Yoshitaka Ishida Kenta Adachi Hayato Murase Dr. Hiroshi Nakagawa Prof.Dr. Takayuki Doi 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(50):18417-18430
The solid‐phase combinatorial synthesis of cyclodepsipeptide destruxin E has been demonstrated. The combinatorial synthesis of cyclization precursors 8 was achieved by using a split and pool method on SynPhase Lanterns. The products were successfully macrolactonized in parallel in the solution phase by using 2‐methyl‐6‐nitrobenzoic anhydride and 4‐(dimethylamino)pyridine N‐oxide to afford macrolactones 9 , and the subsequent formation of an epoxide in the side chain gave 18 member destruxin E analogues 6 . Biological evaluation of analogues 6 indicated that the N‐MeAla residue was crucial to the induction of morphological changes in osteoclast‐like multinuclear cells (OCLs). Based on structure–activity relationships, azido‐containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that 15 b , in which the Ile residue was replaced with a Lys(N3) residue, induced morphological changes in OCLs at a sufficient concentration, and modification around the Ile residue would be tolerated for attachment of a chemical tag toward the target identification of destruxin E ( 1 ). 相似文献
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The Total Synthesis of the Bioactive Natural Product Plantazolicin A and Its Biosynthetic Precursor Plantazolicin B 下载免费PDF全文
Dr. Sabine Fenner Dr. Zoe E. Wilson Prof. Steven V. Ley 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(44):15902-15912
Herein, we describe our full investigations into the synthesis of the peptide‐derived natural product plantazolicin A, a compound that demonstrates promising selective activity against the causative agent of anthrax toxicity, and its biosynthetic precursor plantazolicin B. This report particularly focuses on the challenging preparation of the arginine containing thiazole fragment, including the development of a robust, high yielding procedure that avoids the use of sulfurating agents. Extensive studies on the design of a coherent protecting group strategy and the establishment of a step‐efficient dicyclization/oxidation approach allowed high levels of convergence for the construction of the oxazole fragments. This has led to a unified, highly convergent synthesis for both plantazolicin A and B. 相似文献