Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents

Penthala, Narsimha Reddy; Thakkar, Shraddha; Crooks, Peter A.

doi:10.1016/j.bmcl.2015.05.019

Cited by 21 publications

(8 citation statements)

References 23 publications

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“…Since we expected that the benzothiazole would give similar space occupancy, geometry and polarity intermediate as the replaced rings, and since the colchicine site is known to be somewhat accommodating 16,36 particularly of north ring bicyclic aromatics, we expected that both these Z-SBTubs would bind satisfactorily despite having sacrificed some potencyenhancing point interactions. E-SBTub2 has in fact been reported as a cytotoxic resveratrol analogue targeting tubulin, where its E-geometry was established explicitly and extensive docking simulations were performed to rationalise observed activity 37,38 . However, the E-activity stated in those reports disagrees with our experience 6,39,40 and literature understanding 16 of the requirements of the colchicine binding site.…”

Section: Resultsmentioning

confidence: 99%

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Gao

Kraus

Wranik

et al. 2019

Preprint

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Here we present GFP-orthogonal optically controlled reagents for reliable and repetitive in cellulo modulation of microtubule dynamics and its dependent processes. Optically controlled reagents ("photopharmaceuticals") have developed into powerful tools for high-spatiotemporal-precision control of endogenous biology, with numerous applications in neuroscience, embryology, and cytoskeleton research. However, the restricted chemical domain of photopharmaceutical scaffolds has constrained their properties and range of applications. Styrylbenzothiazoles are an as-yet unexplored scaffold for photopharmaceuticals, which we now rationally design to feature potent photocontrol, switching microtubule cytoskeleton function off and on according to illumination conditions. We show more broadly that this scaffold is exceptionally chemically and biochemically robust as well as substituent-tolerant, and offers particular advantages for intracellular biology through a range of desirable photopharmaceutical and drug-like properties not accessible to the current classes of photoswitches. We expect that these reagents will find powerful applications enabling robust, high precision, optically controlled cell biological experimentation in cytoskeleton research and beyond. Introduction:Molecular photoswitches have been used to install optical control over a broad range of phenomena, with applications from material sciences 1,2 through to reversible photocontrol of ligand binding affinities 3 and manipulation of diverse cellular processes in chemical biology 4,5 . For studies of temporally-regulated and spatially anisotropic biological systems, particularly those that simultaneously support several cellular functions, photoswitchable inhibitors conceptually enable a range of powerful studies not accessible with other tool systems. [6][7][8] A prime example of such spatiotemporally regulated, multifunctional systems is the microtubule (MT) cytoskeleton. This complex cellular network plays central roles in nearly all directed mechanical processes, such as intracellular transport and cell motility; its crucial function in cell proliferation has also made it a central anticancer drug target. 9-11 Yet, whereas cytoskeleton research typically aims to study a subset of MT-dependent processes that are spatially and/or temporally localised, nearly all MT inhibitors reported as tool compounds for biological research are drugs that are active wherever they are distributed, including at sites and at times where drug activity is not desired. 12 This restricts the scope of applications and utility of these inhibitors for selective research into the various, highly dynamic, anisotropic processes dependent on MTs. 13 The structure of the colchicine site MT inhibitor combretastatin A-4 (CA4; Fig 1a) 14 has recently inspired photoswitchable solutions to the problem of achieving spatiotemporal control over MT inhibition. CA4 is a stilbene whose Z-isomer (cis) binds tubulin, acts as a low nanomolar cytotoxin in cellulo, and reached Phase III trials as an ...

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Section: Resultsmentioning

confidence: 99%

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Gao

Kraus

Wranik

et al. 2019

Preprint

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“…65 The stilbenes 36, 37 have showcased potent inhibition to the growth of human cancer cells. 66 The antioxidant and anti-carcinogenic pterostilbene 38 67 was synthesized in 64% yield via the Suzuki-Miyaura coupling of the boronate ester 17 and 4bromophenol. The methyl deprotection of pterostilbene 38 furnished anti-carcinogenic drug resveratrol 39.…”

Section: Scope Of Manganese Catalyzed Acceptorless Dehydrogenative Bo...mentioning

confidence: 99%

Manganese catalyzed acceptorless dehydrogenative borylation of styrenes

Das

Kundu

Adhikari

et al. 2022

Preprint

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Alkenyl boronate esters are important synthons for various pharmaceuticals, agrochemicals, natural products, and material science. Direct alkene sp2 C-H bond borylation is highly valued for its synthesis. However, the drawbacks associated with chemo-, regio- and stereoselectivity, using late transition metal catalysts, and the need for sacrificial hydrogen scavengers impeded its practicability and sustainability. Herein, we utilized a 3d metal complex as a catalyst for synthesizing alkenyl boronate esters via the dehydrogenative coupling of styrenes and pinacolborane. Hydrogen gas is produced as the sole byproduct without needing an acceptor, making the process green and atom-economical. The methodology depicted excellent selectivity towards dehydrogenative borylation over direct hydroboration. Borylation of aromatic alkenes over aliphatic ones was also noticed. Derivatives of natural products and bioactive molecules underwent successful diversification. The product alkenyl boronate esters could be employed for synthesizing several drugs and potential anticancer agents. Thorough experimental and high-level computational studies were performed to delineate the reaction pathway. The hemilability and metal-ligand bifunctionality of the ligand backbone was found to be crucial for successful catalytic turnover.

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“…In a recent study, heteroaromatic analogues of 1 were evaluated for their anticancer activity against a panel of 60 human cancer cell lines (NCI‐60 panel) at a concentration of 10 −5 m . In these compounds, the 4‐methoxyphenyl moiety in compound 1 was replaced with a heterocyclic ring such as indole, benzofuran, benzothiazole, and benzothiophene and the methoxy substitution pattern was also varied.…”

Section: Synthetic Anticancer Stilbenesmentioning

confidence: 99%

“…Pyridine stilbenes substituted at C4 and an ortho or meta methoxy group in the benzene ring, such as compound 32 (Figure 9), showed an action similartor esveratrol. [101] In ar ecent study,h eteroaromatic analogues of 1 were evaluated for their anticancer activity against ap anel of 60 human cancer cell lines (NCI-60 panel) at ac oncentration of 10 À5 m. [102] In these compounds, the 4-methoxyphenyl moiety in compound 1 was replaced with ah eterocyclic ring such as indole, benzofuran, benzothiazole, andb enzothiophenea nd the methoxy substitution pattern was also varied. The combination of (E)-3,4,5-trimethoxystyryl moiety and benzothiazole or benzothiophene, respectively (compounds 33 and 34,F igure 9), exhibited the most potent growth inhibition against most of the tested cancer cell lines and this strongest binding interaction at the colchicine-bindingsite on tubulin was studied by molecular modeling studies.…”

Section: Heteroaromatic Stilbenesmentioning

confidence: 99%

Anticancer Activity of Stilbene‐Based Derivatives

et al. 2017

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Stilbene is an abundant structural scaffold in nature, and stilbene-based compounds have been widely reported for their biological activity. Notably, (E)-resveratrol and its natural stilbene-containing derivatives have been extensively investigated as cardioprotective, potent antioxidant, anti-inflammatory, and anticancer agents. Starting from its potent chemotherapeutic activity against a wide variety of cancers, the stilbene scaffold has been subject to synthetic manipulations with the aim of obtaining new analogues with improved anticancer activity and better bioavailability. Within the last decade, the majority of new synthetic stilbene derivatives have demonstrated significant anticancer activity against a large number of cancer cell lines, depending on the type and position of substituents on the stilbene skeleton. This review focuses on the structure-activity relationship of the key compounds containing a stilbene scaffold and describes how the structural modifications affect their anticancer activity.

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Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents

Cited by 21 publications

References 23 publications

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Manganese catalyzed acceptorless dehydrogenative borylation of styrenes

Anticancer Activity of Stilbene‐Based Derivatives

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