Grand Challenge Commentary: Accessing new chemical space for 'undruggable' targets

Dandapani, Sivaraman; Marcaurelle, Lisa A.

doi:10.1038/nchembio.479

Cited by 193 publications

(160 citation statements)

References 15 publications

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“…[1][2][3] The construction of an ent-kaurane diterpenoids library was initiated by our group in 1976, and more than 1000 pure ent-kauranoids, which includes more than 700 novel discoveries, have been identified from Isodon genus. 4,5 As one of the important plants of Isodon genus, I. eriocalyx var.…”

Section: Introductionmentioning

confidence: 99%

Four new diterpenoids from Isodon eriocalyx var. laxiflora

Wang

et al. 2013

Nat. Prod. Bioprospect.

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Four new diterpenoids, laxiflorins S-V (1-4), bearing four different types, and one known compound, laxiflorin O (5), were isolated from Isodon eriocalyx var. laxiflora. Compound 1 was the first example of ent-kauranoids bearing a unique C 24 carbon framework and compound 4 was the first example of 3,4-seco-ent-abietane diterpenoids from the Isodon genus. Their structures were determined by spectroscopic methods (UV, IR, MS, NMR).

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Section: Introductionmentioning

confidence: 99%

Four new diterpenoids from Isodon eriocalyx var. laxiflora

Wang

et al. 2013

Nat. Prod. Bioprospect.

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“…S tructural diversity has a profound impact on the performance of a compound collection exposed to biological screenings [1][2][3] . Probe and drug discovery research, therefore, beseech quality-based compound libraries rich in structural diversity 4,5 .…”

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confidence: 99%

De novo branching cascades for structural and functional diversity in small molecules

et al. 2015

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The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero-or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

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“…Typically small molecules in the drug discovery research are rich in sp 2 character, 6,7 whereas natural products 8 that have an excellent track record in the domain of biomacromolecular interactions are relatively complex in nature and present a diverse array of chiral functional groups. In particular, macrocyclic natural products 9 are proven to exhibit remarkable biological responses when it comes to modulating ppi through small molecules.…”

mentioning

confidence: 99%

Tetrahydroquinoline-Derived Macrocyclic Toolbox: The Discovery of Antiangiogenesis Agents in Zebrafish Assay

Guduru

Chamakuri

Chandrasekar

et al. 2013

ACS Med. Chem. Lett.

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A novel approach to incorporate the macrocyclic rings onto the privileged substructure, i.e., tetrahydroquinoline scaffold, is developed. The presence of an amino acid-derived moiety in the macrocyclic skeleton provides an opportunity to modulate the nature of the chiral side chain. Further, evaluation in a zebrafish screen identified three active small molecules (2.5b, 3.2d, and 4.2) as antiangiogenesis agents at 2.5 μM.

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Grand Challenge Commentary: Accessing new chemical space for 'undruggable' targets

Abstract: The synthesis and biological annotation of small molecules from underexplored chemical space will play a central role in the development of drugs for challenging targets currently being identified in frontier areas of biological research such as human genetics.

Cited by 193 publications

References 15 publications

Four new diterpenoids from Isodon eriocalyx var. laxiflora

Four new diterpenoids from Isodon eriocalyx var. laxiflora

De novo branching cascades for structural and functional diversity in small molecules

Tetrahydroquinoline-Derived Macrocyclic Toolbox: The Discovery of Antiangiogenesis Agents in Zebrafish Assay

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