Recent Developments Towards the Synthesis of Varitriol: An Antitumour Agent from Marine Derived Fungus Emericella Variecolor

Abstract

Marine natural product is recognized as a fruitful source of drug development due to their rare structural entities and diverse biological activities, and consequently, publicized number of metabolites as new medicines. Although extensive progress has been made in identifying novel bioactive molecules from marine source, great endeavor are still needed to explore these molecules for medicinal applications. Marine fungi are one of the important source of natural products, exhibiting a wide range of biological activities. (+)-Varitriol, isolated from the marine fungus Emericella variecolor, has shown 100-fold increased potency over the mean toxicity towards variety of cancer cell lines. Hence (+)-varitriol, an antitumour marine natural product has been a fascinating target for total synthesis over the last decade. The intense search for developing new approaches coupled with its biological activity has resulted in a wealth of methods towards the synthesis of this molecule. But, unfortunately only limited analogues have been synthesized and evaluated for their biological activities. Thus, there are still demands to modify aromatic part as well as sugar moiety of varitriol, which could provide the opportunity for further SAR studies to discover potential lead anticancer agents. This review describes the different strategies developed for the synthesis of varitriol and its analogues in various laboratories around the world covering literature from 2002 till date. The construction of challenging fashionable furanoside ring as well as substituted styrene derivatives are crucial steps in most of the reported synthetic endeavors.

Stereocontrolled Nucleophilic Addition to Five-Membered Oxocarbenium Ions Directed by the Protecting Groups. Application to the Total Synthesis of (+)-Varitriol and of Two Diastereoisomers Thereof

“…for 298.16545 [M + NH 4 ] + : C 15 H 24 NO 5 ; found: 298.16498. The spectroscopic data fully matched with those reported in the literature. ,, …”

“…This compound has shown important cytotoxic activity against renal, central nervous system, and breast cancer cell lines . The biological activity shown by 31 has attracted the attention of the synthetic community, and 12 total syntheses have been published so far. − Also, due to its important biological activity and lack of a complete understanding of the action mode of this natural product, the preparation of diastereoisomers of varitriol has also been a constant subject in recent years . By taking advantage of the stereodiergent C-glycosidation of l -xylose drivatives, we envisaged to synthesize 5′- epi -(+)-varitriol ( 32 ) and 3′,5′- epi -varitriol ( 33 ), two diastereoisomers of the natural product (Scheme ).…”

Benzyl Alcohol/Salicylaldehyde-Type Polyketide Metabolites of Fungi: Sources, Biosynthesis, Biological Activities, and Synthesis

“…Since the first synthesis [ 15 ] of the unnatural enantiomer (−)- 1 , accomplished by Jennings in 2006, about 22 total syntheses of varitriol have been reported in the literature. The review by Majik et al [ 16 ] described different synthetic approaches towards 1 and its analogues in detail, covering the period up to 2013. The first two synthetic approaches commencing from d -ribose provided unnatural varitriol ((−)- 1 ) ( Scheme 2 ) [ 15 ].…”

The Essentials of Marine Biotechnology

“…The increasing standard of life inherently represents a growing demand for pharmaceuticals, nutraceuticals and cosmeceuticals. Marine organisms, such as algae, sponges, mollusks (including cone snails), cyanobacteria, actinobacteria, fungi, tunicates and fish biosynthesize metabolites with significant biological activities for therapeutic and industrial applications, with anticancer, anti-inflammatory, anti-and pro-osteogenic, antiobesity, antimicrobial, antiviral, and anticoagulant activities (Majik et al, 2014;Surget et al, 2017;Carson et al, 2018a,b;Jin Q. et al, 2018;Kumar, 2019;Mayer et al, 2020). To date, seventeen clinically approved drugs of marine origin include: cytarabine (Cytosar-U R ), nelarabine (Arranon R ), fludarabine phosphate (Fludara R ), trabectedin (Yondelis R ), eribulin mesylate (Halaven R ), brentuximab vedotin (Adcetris R ), plitidepsin (Aplidin R ), polatuzumab vedotin (Polivy TM ), enfortumab vedotin-ejfv (PADCEV TM ), and more recently, lurbinectedin (Zepzelca R ) and belantamab mafodotin (BLENREP R ) for cancer treatment, ziconotide (Prialt R ) for severe chronic pain, ω-3acid ethyl esters (Lovaza R ), eicosapentaenoic acid ethyl ester (Vascepa R ), and ω-3-carboxylic esters (Epanova R ) for hypertriglyceridemia treatment, and ι-carrageenan (carragelose) and vidarabine (Vira-A R ; US discontinued 17 ) for antiviral treatment (Martins et al, 2014;Jimenez et al, 2020).…”