Polynuclear Platinum Drugs
Astrid Sigel, Helmut Sigel in Metal Ions in Biological Systems, 2004
The sequence preference for II, III and IV on plasmid DNA was determined to the exact base pair and strong sequence preference for single dG or d(GG) sites was found [39a,47]. The presence of relatively few blocks on DNA in comparison to either cisplatin or I was indicative of higher sequence selectivity. In comparing the sequence preference for the polyamine-bridged compounds, some stop sites unique to the 4+ compounds II and III were seen but, in general, the preferences were very similar. By choosing an appropriate sequence where stop sites occurred, molecular modeling suggested various possible adducts including 1,4-and 1,6-(G,G) interstrand and 1,5-(G,G) intrastrand cross-links, which were similar in energy (Figure 6) [39].
Cyclic, Conformationally Constrained Melanotropin Analogs: Structure-Function and Conformational Relationships
Mac E. Hadley in The Melanotropic Peptides, 2018
The high potency of the cyclic cysteine-bridged compounds has spurred considerable interest as to the conformational structure features of the molecule that lead to this enhanced potency. Since the molecule is conformationally restricted by virtue of the disulfide bridge, it lends itself to a more critical analysis of conformational structure-biological activity relationships. Various features of the cyclic molecule that may be responsible for these biological properties have been examined.
Bioactive cyclic molecules and drug design
Published in Expert Opinion on Drug Discovery, 2018
RiPPs not only occur in the marine environment but also in terrestrial sites, as this basic biosynthetic mechanism was identified as the source of nisin, which had been known for many years. In addition, some of the well described fungal toxins that had been known for many years, are now recognized as being produced by this mechanism, including the extremely toxic amatoxins from the ‘death cap mushroom’ Amanita phalloides, which cross the gut and inhibit RNA polymerase II with the biosynthetic mechanism reported in 2007[23]. As with other RiPPS they start with, in this case, a 35 aminoacid precursor and end up as a cyclic structure from 8 aminoacids with a similar backbone but differing substitution at five sites. As shown in Figure 67, the basic structure can be considered as at least a bicyclic molecule which binds at the bridge helix of the RNA Pol II complex, locking it in place and slowing the activity from thousands of nucleotides processed per minute to a few. Currently, nine compounds have been identified with others underway, all being simple substitutions at one or more of five positions. As with other microbes that produce toxic molecules, the target protein in the producer is mutated so that the toxins do not cause death of the producer[24].
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