Chemical Interference of Biological Systems with Natural Products

Abstract

Chemical compounds isolated from natural sources offer unique opportunities to understand life on a molecular level. In this account, an overview over different natural products investigated in our research group over the last decade is presented. We have shown that protein localization in living cells can be controlled by anguinomycins and derivatives. Furthermore, a truncated analog, SB640, was discovered that retained much of the natural product potency. Detailed studies of the iron chelator anachelin led to the development of a bio-inspired platform for the generation of bioactive interfaces. The discovery of natural products isolated from cyanobacteria such as nostocarboline, aerucyclamides, cyanopetolin 1020 and various microcystins is presented and their molecular mechanisms of action were investigated. The last part describes the synthesis and evaluation of various natural products involved in neuritogenesis and synapse reconstruction such as withanolide A, militarinone, farinosone A and C and torrubiellone C. Their potential with regard to their use in regenerative medicine is discussed.

Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds – A Computational “Proof-of-Concept”

“…This implies that the modification of Ang-D into SB640 caused a significant reduction in molecular weight, size and volume, which could in turn enhance intestinal absorption and cellular uptake with respect to pharmacokinetic activity. This was in line with previous experimental studies which reported ~60% reduction in size [ 24 , 47 ]. The influence of a relatively high MW on Ang-D relative to bioactivity is further reflected by the number of rotatable bonds which is a good descriptor of molecular flexibility [ 97 ].…”

“…This technique enables the synthesis of tailored bioactive fragments with reduced molecular weight and structural complexity when compared to the parent bioderived compound [ 14 ]. Moreover, while the number of synthetic steps is significantly reduced, resulting fragments retain drug activity or even exhibit improved bioactivity and selectivity [ 14 , 23 ]. The biological significance of this synthetic method is that it allows for the removal of multi-functional groups that are redundant and not essential for binding interactions with target proteins but rather enhance off-target interactions with biological non-targets which engender toxic responses [ 14 , [24] , [25] , [26] ].…”

“…Moreover, while the number of synthetic steps is significantly reduced, resulting fragments retain drug activity or even exhibit improved bioactivity and selectivity [ 14 , 23 ]. The biological significance of this synthetic method is that it allows for the removal of multi-functional groups that are redundant and not essential for binding interactions with target proteins but rather enhance off-target interactions with biological non-targets which engender toxic responses [ 14 , [24] , [25] , [26] ]. In other words, the implementation of this concept may unveil a new route towards innovative drug discovery since not all chemical substituents present in bioderived compounds are required for bioactivity [ [27] , [28] , [29] ].…”

“…Moreover, since CRM1-dependent transport affects cancer-related proteins that bear the canonical NES, the idea of antagonizing these pro-carcinogenic associations presents a promising strategy in cancer therapy. Over the years, this therapeutic strategy has been augmented with the discovery of potent natural compounds that selectively target CRM1 and block mediated export [ 24 , 31 , 32 , 40 ]. These compounds include Leptomycin B (LMB) [ 41 ], Anguinomycin [ 40 , 42 ] and Ratjadone A [ 43 , 44 ], which have a common α,β-unsaturated δ-lactone ring ( Fig.…”

“…Surprisingly, a truncated analogue of Ang-D, SB640 was shown to exhibit an unexpectedly stronger inhibition towards CRM1 than its parent compounds and other synthetic analogues [ 31 , 40 ]. As reported, its synthesis involved a significant reduction in the molecular size and weight of Ang-D (nearly 60%) while it still retained its CRM1-inhibitory activities coupled with improved bioavailability, solubility and reduced toxicity [ 24 , 47 ]. Structurally, the presence of the long polyketide chain distinguishes Ang-D from SB640, which has its polyketide chain (tail) completely removed, majorly constituting the conjugate acceptor, α,β-unsaturated δ-lactone ring [ 40 , 42 ] ( Fig.…”