https://www.science.org/content/blog-post/these-are-real-compounds Advertisement * * news * careers * commentary * Journals * Covid-19 Science Science * * * Log in * Become A Member [science] science [sciadv] science advances [sciimmunol] science immunology [scirobotic] science robotics [signaling] science signaling [stm] science translational medicine [spj-cover] science partner journals Quick Search anywhere Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Searching: Anywhere AnywhereScienceScience AdvancesScience ImmunologyScience Robotics Science SignalingScience Translational Medicine Advanced Search Search Trending Terms: * covid-19 * climate * science policy * genome editing * batteries Log In Become A Member Quick Search anywhere Enter Search Term[ ] science.org * Custom publishing * collections * videos * podcasts * blogs * visualizations * prizes and awards * authors & reviewers * librarians * advertisers * about * help * * * * * * AAAS Logo * Terms of Service * Privacy Policy * Accessibility * Commentary Home * Opinion * Analysis * Blogs GET OUR E-ALERTS HomeCommentaryBlogsIn the PipelineThese Are Real Compounds Back To In the Pipeline * In the Pipeline These Are Real Compounds * 23 Mar 2022 * By Derek Lowe * 2 min read * Comments Share: * Twitter * Linked In * Facebook * Reddit * Email It's been a while since the last post here on crazy natural product structures, so let's do some more. [ladderanoic]First up is ladderanoic acid, which is just one of a whole family of natural product "ladderanes". These were first isolated from some rather weird bacteria, anaerobic species that oxidize ammonium ions (and nitrite) to nitrogen gas. They have particular compartments where this nasty process takes place (hydrazine and hydroxylamine are intermediates, and these are rather toxic things for a living creature to be handling), and the membranes around this space are enriched in ladderane lipids. I don't think they've been found anywhere else in nature, and why these bacteria hit on these structures is a mystery. But they apparently do the job, and that's enough for evolution! This recent review will catch you up on the latest speculations. There have been a number of syntheses of such structures, generally involving a lot of photochemistry, which has long been the go-to for assembling four-membered rings. [lomaiviticin]Next up are the lomaiviticins (and a related group called kinamycins). That's lomaiviticin A shown, and that's the latest structural revision (as of last year). As you'd imagine, pinning all that down is not so trivial. I'll draw ladderanoic acid out in ChemDraw, but I refuse to redraw this beast! It looks fearsome from here, but natural products types will immediate recognize the various sugars and amino-sugars hanging off of the core. But that core is pretty weird by itself - two flat quinone thingies attached to each other. Even that is the sort of thing you'll find in other natural products, more or less, but then you get to the diazo groups (!) in the middle of the whole thing. Now that's unusual. Synthetic organic chemists use diazo chemistry, but these things tend to be rather reactive (and in small molecules can be hazardous as well. The simplest one (diazomethane) is a well-known explosion hazard when it gets concentrated, being set off by things like ground glass joints and similar intolerable stimuli. And it's also extremely toxic, a property that sometimes gets forgotten due to the all the explosiveness. The trimethylsilyl version of the reagent is much less sensitive but still extremely toxic, and that disconnect has led to tragedy. Lomaiviticin itself is extremely cytotoxic, and painstaking work has shown that those twin diazo groups are involved in a double-strand DNA breakage mechanism. Now feast your eyes on leptocillin (MK4588), which is a much smaller thing, but well stocked with weirdness. That four-membered ring fused with a hydroxy, OK, not normal, but then you hit the two isocyanides. That's an unusual functional group for a natural product, and is actually an unusual function group for anything. As a class, those compounds are (in)famous for their hideous and difficult-to-describe smell, and I would guess that leptocillin makes its presence known - or would, if you had it in any quantity. Here's another natural product di-isonitrile if you can't get enough of them. There are even compounds that feature isocyanides right next to epoxides, which I would not want to try to make (not sure how to make one of them without the other falling apart!) [leptocillin] As you'd guess from the name, the compound has antibiotic properties, and that's common to isocyanides in general. Their natural products seem to be invariably in the chemical-warfare category, with bacteria and fungi all trying to kill each other off to make room. Here's a review on their medicinal chemistry, making an argument that the whole class has been neglected by drug discoverers because of worries about toxicity. That's probably fair, but to be honest, I think the other big reason is that no one can stand to be in the same lab with the damn things. [sceptrin] Finally, let's have a look at sceptrin. That's a marine natural product from a sponge (protip: whenever you see a bromine in a natural product, it's almost always from some salt-water creature). That's rather strange to have a tetrasubstituted cyclobutane in the middle of a compound like that, but it does have some symmetrical eye appeal. That motif does show up from time to time, and almost always with such symmetry, which gives some clues about the biosyntheses involved. There are a number of other pyrrole/imidazole compounds like that in nature, but this is probably the snazziest. It's been synthesized, and it's been investigated for its effects on cellular motility (which do not seem to be toxicity-related, and to the best of my knowledge have not yet been completely worked out). It's also been reported to bind to the bacterial protein MreB, but longtime chem-blog readers will find some interest in the author list of that paper as well (!) About the author Derek Lowe Derek Lowe emailTwitter Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. --------------------------------------------------------------------- Comments Please enable JavaScript to view the comments powered by Disqus. IN THE PIPELINE Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog, all content is Derek's own, and he does not in any way speak for his employer. 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