Total Synthesis of (−)‐Caprazamycin A

Nakamura, Hakobu; Tsukano, Chihiro; Yasui, Motohiro; Yokouchi, Shinsuke; Igarashi, Masayuki; Takemoto, Yoshiji

doi:10.1002/ange.201411954

Cited by 12 publications

(8 citation statements)

References 59 publications

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“…To date, several derivatives of uridylpeptide natural products have been generated through engineering of the organisms that produce the natural products or through semi-synthetic approaches and, as such, feature limited structural variation 17 18 19 20 21 22 23 24 25 . A number of synthetic studies have also been reported on uridylpeptide natural products and analogues 26 27 28 29 30 31 32 33 , some of which have been shown to possess antimicrobial activity 7 8 . The focus of the present study was to develop a rapid and divergent synthetic strategy to access a diverse library of sansanmycin analogues that would enable the determination of key structure-activity relationships specifically against Mtb.…”

Section: Resultsmentioning

confidence: 99%

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

et al. 2017

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Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

et al. 2017

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“…[27][28][29] However, until recently, the final complex compound of a caprazamycin family member, caprazamycin A (19, Scheme 1), including the unstable long chain acyl tail modification, had proven synthetically inaccessible. The first total synthesis of (−)caprazamycin A was performed by Takemoto and co-workers in 2015, 30 and the synthesis was further developed in 2019. 31 2.1.1 A recent total chemical synthesis of a complex uridine natural product -Challenges from previous efforts towards caprazamycin natural products (19) involved construction of the syn-b-hydroxyamino acid moiety, formation of the 1,4-diazepanone core, and the introduction of the fatty acid side chain (Scheme 1).…”

Section: Caprazamycinmentioning

confidence: 99%

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

Arbour

Imperiali

2020

Bioorganic & Medicinal Chemistry

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Nucleoside derivatives, in particular those featuring uridine, are familiar components of the nucleoside family of bioactive natural products. The structural complexity and biological activities of these compounds have inspired research from organic chemistry and chemical biology communities seeking to develop novel approaches to assemble the challenging molecular targets, to gain inspiration for enzyme inhibitor development and to fuel antibiotic discovery efforts. This review will present recent case studies describing the total synthesis and biosynthesis of uridine natural products, and de novo synthetic efforts exploiting features of the natural products to produce simplified scaffolds. This research has culminated in the development of complementary strategies that can lead to effective uridine-based inhibitors and antibiotics. The strengths and challenges of the juxtaposing methods will be illustrated by examining select uridine natural products. Moreover, structure-activity relationships (SAR) for each natural product-inspired scaffold will be discussed, highlighting the impact on inhibitor development, with the aim of future uridine-based small molecule expansion.

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“…The total synthesis of caprazamycin A has been reported and was accomplished in 23 steps. It will guide the synthesis of related uridyl liponucleoside antibiotics such as liposidomycin and A-90289 [77,78]. Although an analog of caprazamycin, CPZEN-45, has been anticipated as a new antituberculosis drug, the co-crystal structures of caprazamycin analogs to MraY and WecA will also provide information about other new potential drugs (Fig.…”

Section: Organic Synthesis and Biosynthesis Of Liponucleoside Antibiomentioning

confidence: 99%

Liposidomycin, the first reported nucleoside antibiotic inhibitor of peptidoglycan biosynthesis translocase I: The discovery of liposidomycin and related compounds with a perspective on their application to new antibiotics

Kimura

2019

J Antibiot

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Liposidomycin is a uridyl liponucleoside antibiotic isolated from Streptomyces griseosporeus RK-1061. It was discovered by Isono in 1985, who had previously isolated and developed a related peptidyl nucleoside antibiotic, polyoxin, a specific inhibitor of chitin synthases, as a pesticide. He subsequently isolated liposidomycin, a specific inhibitor of bacterial peptidoglycan biosynthesis from actinomycetes, using a similar approach to the discovery of polyoxin. Liposidomycin has no cytotoxicity against BALB/3T3 cells but has antimicrobial activity against Mycobacterium spp. through inhibition of MraY (MurX) [phospho-N-acetylmuramoyl-pentapeptide transferase (translocase I, EC 2.7.8.13)]. Since the discovery of liposidomycin, several liposidomycin-type antibiotics, including caprazamycin, A-90289, and muraminomycin, have been reported, and their total synthesis and/or biosynthetic cluster genes have been studied. Most advanced, a semisynthetic compound derived from caprazamycin, CPZEN-45, is being developed as an antituberculosis agent. Translocase I is an interesting and tractable molecular target for new antituberculosis and antibiotic drug discovery against multidrug-resistant bacteria. This review is dedicated to Dr Isono on the occasion of his 88th birthday to recognize his role in the study of nucleoside antibiotics.

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Total Synthesis of (−)‐Caprazamycin A

Cited by 12 publications

References 59 publications

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

Liposidomycin, the first reported nucleoside antibiotic inhibitor of peptidoglycan biosynthesis translocase I: The discovery of liposidomycin and related compounds with a perspective on their application to new antibiotics

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