Design, Synthesis and Pharmacological Evaluation of Noscapine Glycoconjugates

Mishra, Kunj B.; Tiwari, Vinod K.; Bose, Priyanka; Singh, Rajan; Rawat, Arun K.; Singh, Sukhmehar; Mishra, Rupesh K.; Singh, Rakesh Kumar; Tiwari, Vinod

doi:10.1002/slct.201803588

Cited by 19 publications

(21 citation statements)

References 42 publications

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“…The biosynthesis of noscapine ( 5 ) starts from l ‐tyrosine ( 6 ) and proceeds via the intermediate reticuline ( 7 ). Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted [90–102,105,106,108] …”

Section: Engineering Anti‐inflammatory Natural Productsmentioning

confidence: 99%

“…In the past 10 years, several attempts have been made to generate noscapine analogues with favorable properties. [91][92][93][94][95][96][97][98][99][100][101][102] As a consequence of the complex stereochemistry, total chemical syntheses of noscapinoids are hard to realize. Therefore, semisynthesis has become the method of choice.…”

Section: Noscapinementioning

confidence: 99%

“…Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted. [90][91][92][93][94][95][96][97][98][99][100][101][102]105,106,108] The biotechnological production of noscapine analogues became possible following the discovery and characterization of its biosynthesis gene cluster in the opium poppy. [103,104] The natural assembly of 5 is extremely complex.…”

Section: Noscapinementioning

confidence: 99%

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Bioengineering of Anti‐Inflammatory Natural Products

2020

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Inflammatory processes occur as a generic response of the immune system and can be triggered by various factors, such as infection with pathogenic microorganisms or damaged tissue. Due to the complexity of the inflammation process and its role in common diseases like asthma, cancer, skin disorders or Alzheimer's disease, anti‐inflammatory drugs are of high pharmaceutical interest. Nature is a rich source for compounds with anti‐inflammatory properties. Several studies have focused on the structural optimization of natural products to improve their pharmacological properties. As derivatization through total synthesis is often laborious with low yields and limited stereoselectivity, the use of biosynthetic, enzyme‐driven reactions is an attractive alternative for synthesizing and modifying complex bioactive molecules. In this minireview, we present an outline of the biotechnological methods used to derivatize anti‐inflammatory natural products, including precursor‐directed biosynthesis, mutasynthesis, combinatorial biosynthesis, as well as whole‐cell and in vitro biotransformation.

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Section: Engineering Anti‐inflammatory Natural Productsmentioning

confidence: 99%

Section: Noscapinementioning

confidence: 99%

Section: Noscapinementioning

confidence: 99%

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Bioengineering of Anti‐Inflammatory Natural Products

2020

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“…This motif is a common functionality found in natural products such as the 1) and noscapinoids 2-5. [14][15][16][17][18][19][20][21][22][23][24] Figure 2. N-Substituted noscapine and multi-functionalised derivatives 6 a-e and 7-9.…”

Section: Introductionmentioning

confidence: 99%

1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure

et al. 2021

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Since the revelation of noscapine's weak anti-mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6', and 9'-positions, though the 1,3-benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3-benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multifunctionalised noscapine derivatives that also possessed modifications previously shown to promote anti-proliferative activity in the 1-, 6'-and 9'-positions. Our research efforts afforded the deuterated noscapine derivative 14 e and the dioxino-containing analogue 20 as potent cytotoxic agents with EC 50 values of 1.50 and 0.73 μM, respectively, against breast cancer (MCF-7) cells. Compound 20 also exhibited EC 50 values of < 2 μM against melanoma, non-small cell lung carcinoma, and cancers of the brain, kidney and breast in an NCI screen. Furthermore, compounds 14 e and 20 inhibit tubulin polymerisation and are not vulnerable to the overexpression of resistance conferring Pgp efflux pumps in drug-resistant breast cancer cells (NCI ADR/RES ). We also conducted X-ray crystallography studies that yielded the high-resolution structure of 14 e bound to tubulin. Our structural analysis revealed the key interactions between this noscapinoid and tubulin and will assist with the future design of noscapine derivatives with improved properties.

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“…Cu-Catalyzed click reaction is a facile and high yielding approach for 1,3-dipolar cycloaddition of organic azides and terminal alkynes which goes well with carbohydrate moiety and has produced very interesting glycosyl triazoles with various applications 14 . Thus, in continuation of our previous experience on click chemistry in glycoscience, [15][16][17][18][19][20][21][22][23][24][25][26][27] this reaction was chosen for cycloaddition reaction of cinchonidine-derived azide and sugar-derived terminal alkynes to achieve our designed target molecules (Fig. 1).…”

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Click Inspired Synthesis of Novel Cinchonidine Glycoconjugates as Promising Plasmepsin Inhibitors

Mishra

Agrahari

Bose

et al. 2020

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Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. the molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins. Malaria has been a medical challenge for centuries mostly in tropical and subtropical countries of the world. Despite significant medical advancement in treatment and prevention of malaria, it still causes thousands of deaths every year 1. The main cause of the disease is protozoan parasite Plasmodium which is generally transmitted by an infected female Anopheles mosquito. Out of five species of Plasmodium responsible for malaria in human, i.e. Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium malariae and Plasmodium ovale, Plasmodium falciparum is the most virulent and accounts most of the deaths caused by malaria. There are several anti-malarial drugs available in markets which act against malaria parasite with different modes of action, but due to rapid spread of drug resistance in malaria parasites mainly Plasmodium falciparum, the need of new antimalarial drug leads is increasing. Plasmepsins, enzymes produced by Plasmodium falciparum, play a key role in hemoglobin-degrading activity of the parasite by export of Plasmodium proteins to the host cell surface 2. Plasmepsin I and II are known to play crucial role in hemoglobin catabolism by cleaving the hemoglobin alpha chain between Phe33 and Leu34 which are located in hinge region which results into dislocation and partial unfolding of globin subunits which further causes more protease sites within the globin polypeptide chains. At this stage, further degradation of large globin fragments takes place by action of plasmepsins and falcipains. In this regards, plasmepsins, which play a key role in the survival of P. falciparum in the host, have emerged as the new effective targets for development of antimalarial drugs with plasmepsin inhibition mode of action. Because of their key functioning in malaria symptoms and consequences, these enzymes are the main target of the anti-malarial drugs 3,4. Recent researches related to anti-malarial drug development have focused plasmepsin inhibition largely 5-8. Thus, the molecules showing inhibitory activities against plasmepsin enzymes can come out to be promising drug leads for treatment of malaria. Cinchona alkaloids are cheap natural source of anti-malarial activity which provides opportunity towards development of new anti-malarial drug leads by synthetic modifications in their chemical structures. The anti-malarial activities of the fo...

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Design, Synthesis and Pharmacological Evaluation of Noscapine Glycoconjugates

Cited by 19 publications

References 42 publications

Bioengineering of Anti‐Inflammatory Natural Products

Bioengineering of Anti‐Inflammatory Natural Products

1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure

Click Inspired Synthesis of Novel Cinchonidine Glycoconjugates as Promising Plasmepsin Inhibitors

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