An Efficient Formal Total Synthesis of Cladosporin

Mohapatra, Debendra K.; Maity, Saurabh; Rao, T. Siva; Yadav, J. S.; Sridhar, B.

doi:10.1002/ejoc.201300053

Cited by 26 publications

(12 citation statements)

References 25 publications

(8 reference statements)

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“…In 2013, Sridhar et al also reported the total synthesis of cladosporin in a highly diasteroselective and concise manner. Cross-metathesis, iodocyclization to construct the trans-2,6disubstituted dihydropyran ring system, and an Alder-Rickert reaction to form the aromatic ring were used as the key steps [34].The complete synthetic methods for production of cladosporin made it amenable to the generation of a group of scaffolds that can potentially be used to improve drug-like properties.…”

Section: Total Synthesis Of Cladosporinmentioning

confidence: 99%

Chemical and Biological Study of Cladosporin, an Antimicrobial Inhibitor: A Review

Wang

Wedge

Cutler

2016

Natural Product Communications

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Natural antifungal agents are generally broad-spectrum compounds with low mammalian and environmental toxicity. Cladosporin is a naturally occurring fungal metabolite mainly isolated from the endophytic fungus Cladosporium cladosporioides. This review article summarizes the chemistry and biological properties of cladosporin covering references published from 1971-2016, including the source, phytochemical characterization, biosynthesis, total synthesis, structure and activity (SAR), and biological activity of cladosporin. Cladosporin exhibited potent antibacterial, antifungal, insecticidal, and anti-inflammatory activities, as well as plant growth regulatory effects. More importantly, cladosporin was identified as having potent, nanomolar, antiparasitic activity against both Plasmodium falciparum blood and liver stages via specific inhibition of protein synthesis. This provides a new approach for the design of isocoumarinbased compounds for the treatment of malaria. Herbicidal activity and antifungal activity against Cryptococcus neoformans (IC 50 value of 17.7 μg/mL) of cladosporin are also described here in the review for the first time. Cladosporin selectively inhibited the growth of a monocot (agostis) and showed no activity against a dicot (lettuce), which indicates its great potential as a selective herbicide for monocots in agriculture use. The above data suggest that cladosporin has great potential utility as a lead compound in the development of agrochemicals against certain plant pathogens and pharmaceuticals against drug-resistant bacteria and parasites.

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Section: Total Synthesis Of Cladosporinmentioning

confidence: 99%

Chemical and Biological Study of Cladosporin, an Antimicrobial Inhibitor: A Review

Wang

Wedge

Cutler

2016

Natural Product Communications

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“…Ni 2+ -nitrilotriacetic acid (NTA) agarose was purchased from Qiagen. Cladosporin, 3-epi-isocladosporin, and isocladosporin were synthesized by Debendra K. Mohapatra, CSIR-Indian Institute of Chemical Technology, Hyderabad, India ( 22 , 23 ). Sypro orange dye was obtained from Sigma.…”

Section: Methodsmentioning

confidence: 99%

“…Heterozygous knockout mutants of Ld LysRS-1 showed reduced growth and were attenuated in their infectivity, indicating the essentiality of this protein. Cladosporin, a fungal secondary metabolite, and 3-epi-isocladosporin, an isoform of isocladosporin ( 22 , 23 ), showed antileishmanial activity in both the promastigote and intracellular amastigote stages in vitro . Both drugs were found to be effective in inhibiting the aminoacylation activity of the recombinant Ld LysRS-1.…”

Section: Introductionmentioning

confidence: 99%

Genetic Validation of Leishmania donovani Lysyl-tRNA Synthetase Shows that It Is Indispensable for Parasite Growth and Infectivity

Chadha

Mallampudi

Mohapatra

et al. 2017

mSphere

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Aminoacyl-tRNA synthetases are housekeeping enzymes essential for protein translation, providing charged tRNAs for the proper construction of peptide chains. These enzymes provide raw materials for protein translation and also ensure fidelity of translation. L. donovani is a protozoan parasite that causes visceral leishmaniasis. It is a continuously proliferating parasite that depends heavily on efficient protein translation. Lysyl-tRNA synthetase is one of the aaRSs which charges lysine to its cognate tRNA. Two different coding sequences for lysyl-tRNA synthetases (LdLysRS) are present in this parasite. LdLysRS-1 is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 is closer to bacteria. Here, we have characterized LdLysRS-1 of L. donovani. LdLysRS-1 appears to be an essential gene as the chromosomal null mutants did not survive. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. This study also provides a platform to explore LdLysRS-1 as a potential drug target.

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“…3 More recently, the total synthesis of cladosporin and its diastereomer, isocladosporin, has been reported 20. 21 To better understand PKS assembly and enable analogue production by synthetic biology, we sought to heterologously express and reconstitute cladosporin expression in Saccharomyces cerevisiae . Hence, we sequenced the genome of the producer, Cladosporium cladosporioides UAMH 5063.…”

Section: Methodsmentioning

confidence: 99%

Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent

et al. 2015

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The anti-malarial agent cladosporin is a nanomolar inhibitor of Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood and liver stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it was believed to be biosynthesized by a highly reducing (HR) and non-reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism, and subsequent heterologous expression of these enzymes in Saccharomyces cerevisiae produced cladosporin, confirming the identity of the putative gene cluster. Incorporation of a pentaketide intermediate analog indicated a 5+3 assembly by the HR PKS Cla2 and the NR PKS Cla3 during cladosporin biosynthesis. A putative lysyl-tRNA synthetase resistance gene was also identified in the cladosporin gene cluster. Analysis of the active site emphasizes key structural features thought to be important in resistance to cladosporin.

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An Efficient Formal Total Synthesis of Cladosporin

Cited by 26 publications

References 25 publications

Chemical and Biological Study of Cladosporin, an Antimicrobial Inhibitor: A Review

Chemical and Biological Study of Cladosporin, an Antimicrobial Inhibitor: A Review

Genetic Validation of Leishmania donovani Lysyl-tRNA Synthetase Shows that It Is Indispensable for Parasite Growth and Infectivity

Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent

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