Bioorganic Studies on the Key Natural Products from Venomous Mammals and Marine Invertebrates

Abstract

The discovery of new bioactive molecules, facilitated by a deeper understanding of nature, will advance our knowledge of biological processes and lead to new strategies to treat disease. Recent technological advancements including spectroscopic analyses and genetic approaches have provided outstanding opportunities for new discoveries, even in the case of scarce, unstable, and composite compounds. This account summarizes two recent aspects of bioorganic chemistry: mammalian venoms and antitumor marine macrolides. Due to the interesting ecology of venomous mammals, we examined the constituents of mammalian venom, and identified unique neurotoxic peptides and kallikrein-like proteases in shrews and platypus. The present findings may lead to the development of valuable vasoactive or pain-relief agents, and to a deeper understanding of the biological evolution of vertebrates in relation to toxic substances. We have also established the target proteins and mode of actions of aplyronine A, a potent antitumor and apoptogenic marine macrolide. The complexity and diversity of actin-targeting natural products might enable them to achieve multiple interactions with as-yet-unidentified biomacromolecules, such as cytoskeleton proteins and focal adhesion proteins, which should offer better perspectives for the design and development of new antitumor drugs.

6-Amidopyrene as a label-assisted laser desorption/ionization (LA-LDI) enhancing tag: development of photoaffinity pyrene derivative

“…It was found that the C34 N -methyl enamide moiety of ApA can be replaced with oximes without a significant loss of activity 35 36 . Also, several PEG-linked biotin conjugates of aplyronines have been shown to retain the potent activity of the natural products 37 38 . Based on these findings, amidopyrene 3 was converted to an alkoxyamine derivative possessing an aryltrifluoromethyldiazirine 39 40 group and a PEG linker, and coupled with ApA C34 aldehyde to afford an aplyronine A photoaffinity amidopyrene derivative (ApA–PaP, 4 ) ( Schemes S2 & S3, Supplementary Information ).…”

Evaluation of the physiological activity of venom from the Eurasian water shrew Neomys fodiens

“…Even several species of toxic birds, such as Pitohui kirhocephalus or Ifrita kowaldi , have been discovered [ 2 ]. However, despite the availability of new proteomic, genomic and chromatographic separation techniques, most venomous and poisonous animals remain unstudied [ 3 – 5 ]. Principally, toxins produced by insects, arachnids, snakes and frogs have been investigated thus far [ 3 , 6 ].…”

“…However, despite the availability of new proteomic, genomic and chromatographic separation techniques, most venomous and poisonous animals remain unstudied [ 3 – 5 ]. Principally, toxins produced by insects, arachnids, snakes and frogs have been investigated thus far [ 3 , 6 ]. Venoms produced by mammals remain mostly uncharacterized [ 3 , 5 , 6 ].…”

“…Principally, toxins produced by insects, arachnids, snakes and frogs have been investigated thus far [ 3 , 6 ]. Venoms produced by mammals remain mostly uncharacterized [ 3 , 5 , 6 ].…”

Antitumor Effects of Sea Hare-Derived Compounds in Cancer

“…In fact, it significantly reduced cellular viability and induced DNA fragmentation at 1 nM in HeLa S3 and human leukemia HL60 cells [79]. In addition, treatment with aplyronine A at 1 nM for 24 h led to potent caspase 3 activation in HeLa S3 cells, while treatment with aplyronine C did not, even at 100 nM [80]. These significant differences in apoptosis-related activities were consistent with their cytotoxicity, which highlighted the importance of the C7 trimethylserine moiety for the potent activities of aplyronine A.…”