Synthesis of novel molecular probes inspired by harringtonolide

Abstract

A novel harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a similar substitution pattern and relative stereochemistry to the complex diterpenoid, has been enumerated into a small library of derivatives. One of these library members has been converted into a sub-library of substituted triazoles using copper-catalysed azide-alkyne cycloaddition (click) chemistry. The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for chemical biology.

Design and synthesis of screening libraries based on the muurolane natural product scaffold

“…NP scaffolds such as the one utilised in this study have the potential to be used as tools for investigating biological pathways and developing novel therapeutics. 3 While the biological activity demonstrated here against P. falciparum is only modest, the library members generated may prove to be 20 useful probes in future screening campaigns against other targets.…”

“…[2][3][4][5][6] Nature remains an untapped source of unique and desirable scaffolds for library production, and subsequent drug discovery. [2][3][4][5][6][7][8] Indeed, numerous scaffolds that have been identified in natural products (NPs) have led to approved drugs or drug candidates for a range of diseases. [7][8][9][10][11][12] Examples include antibacterials (βlactams, tetracyclins, erythromycins), antivirals (modified nucleosides), anticholesterolemics (lovastatin), and anti-tumour agents (paclitaxel, rapamycins, epothilones).…”

Synthesis of naturally occurring tropones and tropolones

“…167 However, they failed to convert the cycloheptatriene products derived from the Buchner reaction to tropones.…”

Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold

“…[7,9] We have previously reported the stereoselective synthesis of the marine natural products, polyandrocarpamines A (1) and B (2), using a high-yielding one-step aldol condensation reaction under microwave conditions. [10,11] Because of our interest in the use of natural products as templates for unique chemical library production, [12][13][14][15][16][17] and the predicted amenability of the new stereoselective microwave chemistry for analogue generation, we herein describe the design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine (2-aminoimidazolone) scaffold. The cytotoxicity of all library members towards three prostate cancer cell lines (LNCaP, PC-3 and 22Rv1) is also reported.…”