Spot-Checking Antibacterials in PLoS One

Update (April 17) - Commenters here and at Derek's place have set off alarm bells to potentially doctored spectra. Stay tuned...
--

Ever looked at a molecule and thought something was just...off?

A little while ago, I browsed through the latest edition of PLoS One, the open science journal. I don't often go there for chemistry publications, but curiosity struck, so I typed, "antibacterial NMR" (I think) into the search box. Up came this paper, from 2013, announcing:

1. A novel alkaloid, xinghaiamine A, isolated from a marine bacterium, that...
2. Had novel structural features, such as a sulfoxide and acenaphthylene ring, rarely seen, and...
3. That showed decent lead activity against MRSA strains (2.7-5.5 uM MIC).

First thought: "Wow!" Second thought: "If this is so great, why is it buried in PLoS One?"

Then I happened to look at the proposed structure for this potential panacea:

Jiao, Zhang, Zhao, Hu, Suh, PLoS One, 2013

[Rubs eyes in disbelief].

Sulfonylated "ladderane" substructure.
A (4,7) disubstituted acenaphthylene bridge.
A previously-unknown-to-science (and virtually unknown to SciFinder) 4-4-5-6 ring system.
Can that really be correct?

Naturally, I made a model of one "half" of the presumed dimeric molecule:

Xinghaiamine A, pseudo-axial conformation,
assumed diastereomer of the (4-4-5-6) ring system.
The red circles are supposed to be bonded together...

I've taken apart and reassembled this molecule a few times, and can't seem to access any diastereomer that 1) looks energetically minimized, and 2) can actually have the acenaphthylene bridge the way the authors specify without "strain energy" popping out the plastic bonds.

Perusing the analyticals in the Supporting Information, I'm puzzled by a few more bits:

Jiao, Zhang, Zhao, Hu, Suh, PLoS One, 2013

The IR, briefly addressed in the text as suggestive of "[the] presence of a sulfoxide functional group" due to the 1082 cm^-1 band, but contains peaks suggestive of:

• alcohols, primary amines: 3383 cm^-1 band
• heteroaromatics: 743, 846 cm^-1 band

The published 1H NMR has no peak labeling or integration (tsk, tsk).

That the COSY shows only one set of strong H/H correlations out of the 6 posited protons on the conjugated ring, which should not fit with the proposed structure. Nor should the seeming high symmetry of the ring fit with the proposed substitution.

--

Readers, what do you make of this? What kept this out of a more mainstream chemistry journal? 

Do you agree with the assigned structure? (Am I just shouting in the wind here?)

April 17 - Uh-oh...check out these anonymous commenters' finds on Derek's blog:

Potential editing of the H/H COSY

...and the HMBC

Fukuyama, Round 2

Update, 4/3/14 - On a hunch, I looked through major publishers' databases for more recent Fukuyama corrections sharing a specific author's name. Found this (Chartelline C) at ACIEE, alleging "[im]properly processed NMR spectra." Since this author published >40 papers with Fukuyama, more may be coming.

ACIEE, 2014 (above) and 2012 (below)

An astute commenter has clued me in to the latest round of corrections coming from the Fukuyama research group (see 1, 2, 3, 4). Targets affected include lyconadins A-C, ecteinascidin 743, and mersicarpine, and publication dates range from 2010-2013. This time, they're in JACS which, to my knowledge, does not (yet) employ a full-time data analyst like Organic Letters does.

The corrections read much the same as the last raft, released two months prior in Org. Lett., alleging spectral manipulation for multiple intermediates and final molecules, including removal of solvent peaks. Here's one example showing 13C spectra* for intermediate 7, from the synthesis of lyconadin A:

Original spectrum (2011)*

Corrected Spectrum (2014)*

Clearly, there's a bunch of "stuff" in 7 that had to be digitally removed by one of the authors. And this is just one compound; each paper contains several such examples of "improperly manipulated" spectra (direct quote!).

So, what's going on here? I have a theory, although it's a bit of hearsay since I'm not privy to the inner workings of either journal. However, the astute reader will note one author whose name appears on nine of the ten corrected papers from Feb-April...uh-oh.

Was there a bad apple in the Fukuyama lab? More details as I have them.

*Apologies for the different shading, due to my computer and not their SI files.

Calimari Calligraphy: Same Ink, 160 Million Years Later

Old news: Geologists, digging up ancient British sea bed, unearth a fossilized cephalopod.


Big news: Its pigment sacs contain the same ink squid still use today!

Fossilized Ink Sac
Source: British Geological Soc. | Nat Geo

This archaeology, with a dash of chemistry for good measure, went to press in PNAS earlier today. As Nat Geo, Discovery News, and msnbc tell it, a stroke of luck brought the multi-national (Japan, India, USA, UK) team a fully intact ink sac, which still contained eumelanin, the ubiquitous black pigment found in skin, hair, and feathers throughout the biological world (for more on the structure and function of melanins, click here).  


Quoth the lead author, John D. Simon (UVA-Charlottesville), to Discovery: 

"Out of all of the organic pigments in living systems, melanin has the highest odds of being found in the fossil record" 

In other words, this collection of highly-oxidized tyrosine and indoleacetic acid residues, chained into polymeric pigments, stays preserved - and structurally sound - for 160 Million Years. Could we say that about most of the materials we make today? Moreover, by comparison of various spectral techniques, the authors wager that the ancient melanin composition looks nearly identical to what squid use today to scare off predators.

IR Data, "flipped"
Source: PNAS Supp Info

Well, I'd like to see some data, wouldn't you? Digging through the Supporting Info, I see loads of evidence: degradation studies, EPR, IR, Mass Spec, CHN analysis, Carbon-13 NMR, UV, pyrrolysis TIC, and X-Ray photoelectron spectroscopy (Whew!). 


Let's examine two of these a little closer. For the IR data, I've switched the view around 180 degrees, to present the peaks the way you'd normally see 'em in the lab. Note the top 2, calcium carbonate and hydroxyapatite, with their nice, sharp C=O and P=O stretching bands. When the researchers looked in the partially-fossilized sediment, they found mostly these two...but look at the dye! Even after all those millennia, the absorbances for the fossil dye line up almost perfectly with the modern-day sample.

Total Ion Chromatogram, Current (top) vs. Fossil (bottom)
Source: PNAS Supp Info

How about a little heat? If you cook the ink at 600 Celsius, then pass it quickly through a mass spec, plotting ion current vs. time, you get the next spectrum, the TIC. It shows the same breakdown products, a variety of small heterocycles and fatty acids, and something I wasn't familiar with: diagenetic products. These products, formed from reactions that occur during fossilization, show up here as sulfur heteorcycles. Since the samples have had quite a bit of time underground, they show much more diagenetic decomposition.