Lab PPE Day is June 4, 2012!

Go check out all the people participating in Lab PPE Day at the official Lab PPE Day Tumblr! Lots of great pictures of chemists that want to participate there, too!

If you'd like to participate and show young chemists that it's normal and common to wear lab PPE, you can Tweet a picture to @LabPPEDay or e-mail a picture to LabPPEDay -at- gmail/dot/com! 

Green Keck clips

A small list of useful things (links):

• Chemtips has a great post on scientific presentations.
• I loved this Wavefunction post on Robert Kirshner's almost-Nobel prize. 
• Josh Bloom responds sharply to a critical comment on his Kristof #chemophobia post. 
• A chemical saved Lab Monkey's bacon.
• I found John's post on patents educational. 
• I also liked this Practical Fragments post on a FBDD review. 
• How does Lisa Balbes run a meeting?
• Taking apart the Grubbs catalysis cycle over at All Things Metathesis. 
• MedChemBuzz is back!
• Missed ScienceGeist's #ToxicCarnival? Check it out, starting here.
• ExxonMobil building a major new plant? Awesome! (Thanks, Teve!) Paul Hodges: US polyethylene manufacturing? DOOOOOOOOOOM. 

Did I miss anything? Have a good weekend!

Unemployment for April up 0.1%, U6 up 0.3%

Credit: Calculated Risk blog

Fresh electrons from the Bureau of Labor Statistics:

The May unemployment rate was up 0.1% from April to 8.2%, and the broader U6 measurement was up 0.3% to 14.8%.

The story today will be the lack of job growth (69k non-farm payroll jobs), and the downward revisions for job growth for March and April. Less talked about will be the slight uptick in the labor force participation rate and the employment-population ratio.

This is not good news, but we knew that already.

Thanks, as always, to Calculated Risk for the graph. 

How many chemists do pharma companies employ?

Did they really have 900 chemists, or did they just
march the same 300 chemists through the courtyard 3 times?
Credit: blindflaneur.com

In 2009, Derek Lowe had this comment about pharma company headcount:

A reader who's (unfortunately) in a position to know the details sends along some numbers on Pfizer's chemistry shakeout. According to his figures, Pfizer (pre-Wyeth merger) had about 900 chemists. The Wyeth deal brought in about 350, but no one expected the merged department to stay at 1250 - instead, the guess was that the new chemistry staff would be in the 1000 range, which is what I would have guessed, too. 

But the chemistry head count is now apparently headed to about 850: smaller than it was before the merger. 

I think it is interesting that it would take someone "in the know" to give a simple headcount of chemists -- then again, I'm not entirely surprised.

If you would have asked me what a typical pharma company's chemist headcount was, I'm not sure I could tell you -- there aren't any really good numbers out there. For the most part, I understand -- Big Pharma is loathe to reveal the details of its R&D spend, and headcount would be a pretty decent proxy. Revealing an exact number of chemists would seem to be unwise, somehow. (There's also the problem of breaking those numbers down: How many analytical chemists? How many associates? How many QC chemists? How many process chemists? Who do they work for -- manufacturing or R&D?)

What is the best way to determine pharma company R&D chemist headcount? Are there proxies that can be used to determine this number? 

This is what a shortage looks like: computer science edition, part 1 of N

From the august pages of the Wall Street Journal:

[snip] Starting salaries at leading companies for average computer science grads from top schools range from $75,000 to $100,000, plus signing and relocation bonuses worth $5,000 to $15,000, according to venture capitalists and recruiters. (New hires may also get small equity grants, with stars getting additional cash bonuses or larger grants worth as much as 1% of the company. 

[snip] Companies, he said, routinely wine and dine students at posh restaurants to discuss internships and jobs, plying them with free limo rides to bars, $500 cash giveaways and raffles for iPads. So many companies give away free food when they hold technology talks at Brown that sponsors had to move the food inside the computer science auditorium to keep non-engineering students from grazing. "That did not deter people," said Mr. Poletto, who accepted a job offer with online storage start-up Dropbox.

What's that I hear? The strains of "Summer Girls" by LFO? Yes! It's just like 1999 for chemists, when I was offered a signing bonus by my first employer because I seemed sort of competent. I'm glad someone is doing well in this economy. (And yes, yet more evidence that STEM is TE.)

Students have differing ideas about career paths at beginning and end of grad school? (Not surprising?)

An interesting study from Nature Jobs:

The study, published on 2 May, surveyed life sciences, physics and chemistry PhD students at various stages of their programmes at top-level US research universities. Respondents in graduate programmes were asked to rate six career options and to recall how they had felt about them at the start of their PhD programme. Although a faculty post was an attractive career path for many students at the start of their programme, this preference slipped as students in all three disciplines advanced in their studies, with chemistry students showing the biggest drop (see 'Losing appeal').

Credit: Nature Jobs

There's a rather wonderful (and perhaps not-so-literally-accurate) quote from one of the co-authors of the study ("Henry Sauermann, a researcher at the College of Management at Georgia Institute of Technology in Atlanta"):

 “It would be nice for other people to provide more information for students, but faculty and advisers don't have that experience,” he says. “You can't expect the chair of the chemistry department to tell you what it's like being a researcher in industry.”

Ooof. Depends on the chair, depends on the department. Still, a blunt (sometimes) truth. 

Daily Pump Trap: 5/31/12 edition

Good morning! Uh, how's it going? Between May 29 and May 30, there were 12 new positions posted on the ACS Careers website. Of these, 7 (58%) are academically connected and 3 (25%) are from Kelly Scientific Resources.

Not much: There's not very much being put out here, with 2 whole positions in the last two days. One of them is not really a position, but...

Not sure what this is: But it sure isn't a job ad:

Custom Synthesis Labs and Academics Interested in Collaborations. We are looking for chemical labs that do custom syntheses and academics interested in increasing their research budgets by doing custom synthesis. See our website: www.medicalisotopes.com to see compounds we are synthesizing. If interested in doing custom syntheses for us, please send us an e-mail at customsynthesis@medicalisotopes.com. Also, describe your field of expertise so we can find projects that are relevant to your field.

The addresses lead to a company called Medical Isotopes, Incorporated. Small company in New Hampshire -- interesting.

Open positions at Pfizer?: We seem to be hitting a lull, so I'm going to randomly look at large pharma and chemical company sites. For the search term "chemist", Pfizer has 3 positions available, 2 R4s (i.e. "senior scientists") and a R5/R6 ("principal scientist"). 2 of these were posted May 15, one posted late March.

Rolla, MO: Our one real job ad of the last two days! It's for a B.S. chemist (with a MBA) to be a technology strategist at Brewer Science, a stalwart of ACS Careers:

Summary: Sets the technological goals/objectives of the business unit and works with the functional area managers to achieve these goals. 

Outcomes: • Brewer Science technology and market leader for every new technology that is brought through the BPD • A clear and concise set of product technology requirements that support the overall corporate goals • Achieve the business unit's objectives by working through the functional area managers 

Specific Responsibilities: • Represents the business unit at customers, suppliers, industry forums and internally • Serve as a technical interface between customers and industry groups and the Business Unit to align development and technical support efforts with their needs and industry trends. • Present pipeline technologies and products to customers through on-site visits and participation at shows and conferences. • Together with division staff, prepare technical presentations and publications. • Develop and manage the intellectual property plan for the Business and supporting R&D division(s). Identify areas for patent protection and work with R&D staff and IA/Legal Groups to ensure timely, comprehensive patent protection of new inventions and future technologies. • Works with functional areas to create area specific objectives, strategies and tactics to achieve the overall business unit technology objectives • Analyzes market information to select specific business and technological targets to achieve the overall business unit objectives • Reviews external documentation to meet the business unit’s goals. • Help drive product/process development by working through the functional area managers.

I'm tempted to offer a cash prize to whomever can translate this stuff.

A broader look: Monster, Careerbuilder, Indeed and USAjobs.gov show (respectively) 290, 807, 3134 and 33 positions for the search term "chemist."

Process Wednesday: Carbon steel versus organic acids

From the pages of Chemical Engineering Magazine, an interesting story about an extraction unit (I think this is somehow related to a petroleum fractionating column?) from Mike Resetarits, the technical director of Fractionation Research, Inc.:

The natural state of the extraction solvent was clear and slightly yellow. With time, however, oxygen would creep into the unit, especially via the vacuum regenerator. Organic acids would form. The acids would eat any carbon steel that they encountered. Iron oxide and carbonaceous materials would accumulate in the solvent, which would turn from yellow to green to brown and then black. Eventually the solvent would look and feel like the three-year-old engine oil in my 1974 Ford Falcon.  

One troubleshooting visit was in response to a complaint about reduced recovery. The unit was shut down for the annual turnaround. My colleague, Reese, and I decided to enter and inspect the extractor at three manhole locations, starting with the top manhole. The top manhole was open. According to our drawings, the top tray was only about 3 ft below the top manhole. We inspected the top tray with our flashlights. It looked fine -- no fouling. Then Reese entered the column feet first, on his belly. He almost fell 20 feet.  

Unfortunately, Reese and I failed to expect the unexpected. The top tray was there -- but it wasn't. It was paper thin. It crumbled to dust instantly under his weight. Fortunately, he was wearing a harness with a lanyard. It turned out that the top ten trays were similarly thin. Replacement trays were provided to the plant on an emergency basis. 

One of the things that I'm encountering as a relatively new process chemist in a manufacturing environment is how much focus there is on the materials of construction of equipment. Most of the time in the lab, your compounds are only going to see one material: glass. But in the plant, glass is relatively rare, it seems, and concerns about the compatibility of whatever metal you might be using with your reaction solvent, reagents and byproducts becomes very important.

One raised eyebrow

In this week's C&EN, an article detailing ACS members' efforts to lobby Congress for more research funding. And what do we read from one of those members?

“I passionately believe that the voice of the scientific community needs to be heard by politicians... Scientific innovation is a key engine that drives the U.S. economy and is vital for our nation’s global competitiveness.”

Good sentiments, one that I might agree with. Who said it?:

[ACS Committee on Chemistry and Public Affairs] member Hui Cai of San Diego, who is vice president of corporate alliances at WuXi AppTec, a global contract research organization. 

Calling WuXi AppTec a "global contract research organization" is sort of like calling the Department of  Defense a "global protective services provider."

Yes, WuXi owns a few facilities in the United States. But let us call it for what it is: a Chinese outsourcing firm that (with its willing Big (and sometimes, small!) Pharma partners) has transferred many medicinal chemistry jobs from the US to China. I find terribly ironic that one of WuXi's employees is lobbying Congress for research funding; doubtless, it's a good deal for WuXi, in that many of their top employees have been trained with US funding. 

Daily Pump Trap: 5/29/12 edition

Good morning! Between May 24 and May 28, there were 42 new positions posted on the ACS Careers website. Of these, 2 (5%) were academically connected and 35 (83%) were from Kelly Scientific Resources.

Hey!: Is anyone else noticing that the ratio of Kelly/non-Kelly positions is really climbing recently? That's a little freaky. Personally, I'm sort of vaguely curious about the "Chemist - Nights and Weekends" position that keeps popping up.

Neat: Merck (Rahway, NJ) is looking for a senior analytical investigator to work with API-related problem solving. Ph.D. in analytical chemistry plus 10 years experience desired.

Newark, DE: Air Liquide is searching for a M.S./Ph.D. research chemist with experience in GC/GC-MS/UV-vis and other spectroscopic techniques. 2+ years experience with environmental monitoring desired.

Boulder, CO: Lexmark desires a Ph.D. chemist with 3-5 years of polymer-related experience to work on "applied research directed at the implementation of emulsion aggregation chemical toners and at carrier coated materials for use in Lexmark laser printer products." If you click through, you'll learn that there's a lot (not that we didn't think so!) to printer ink/toner technology.

Ivory Filter Flask: 5/29/12 edition

Good morning! Between May 21 and May 28, there were 7 academic positions posted on the ACS Careers website. The numbers:

Total number of ads:  8
- Postdocs: 1
- Tenure-track faculty:  3
- Temporary faculty:   2
- Lecturer positions:  0
- Staff positions:  2
- Ratio of US/non-US positions: 5 / 3

Detroit, MI: Wayne State University's School of Pharmaceutical Sciences is looking for a tenure-track assistant professor of medicinal chemistry / drug discovery.

Israel:  The Fulbright Scholars program is looking for postdoctoral fellows in chemistry to work in Israel. Sounds exciting.

Riverdale, NY: Manhattan College (oddly enough, located in the Bronx) is looking for a visiting assistant professor of general chemistry. Like New York? Might be for you!

Denver, CO: Metropolitan State College of Denver is looking for a M.S. chemist to be a lab manager.

St. Cloud, MN: 2 temporary faculty ("one full time and one half-time, fixed-term faculty positions") are available at St. Cloud State University for professors of general chemistry, organic chemistry and biochemistry.

Day off today

Great Lakes National Cemetery (Credit: betterphoto)

It's Memorial Day in the United States, so it's a day off for the blog. Back tomorrow with IFF, DPT and (probably) a little bit of #chemjobs.

Cheers, CJ

Ozymandias, senior med chemist

by Chemjobber

I met a janitor from a run-down lab
Who said: Two vast and peeling poster slides
Hang in the hallway. Near, on the bench slab,
Half torn, a wrinkled photo, with a frown,
And wrinkled lip, and sneer of cold command,
Tell that its subject well those structures read
Which yet survive, inked on these lifeless things,
The hand that drew them in the projects dead:
And on the white caption these words appear:
"Ozymandias, senior med chemist:
Look on my works, ye postdocs, and despair!"
Nothing beside remains. Round the decay
Of that empty building, tragic and bare
The clear hood sashes still rattle away.

with apologies to Shelley

Kindler, Liveris, Madeleine Jacobs all visitors to White House. Chemistry professors? Not really.

The Washington Post has done the country a service by tallying White House visitor logs and putting them in a searchable form.* Being a curious sort, I started to put the names of chemical luminaries into their database.

Disappointingly, I couldn't get any prominent professors of organic chemistry. Sanford, Jacobsen, Bertozzi and Breslow were all busts. (Maybe they were one of the people who didn't have to sign in, yeah, that's the ticket!) Daniel Nocera is a no-go, too. (See update below.)

Among pharma types, (your friend and mine!) Jeff Kindler has been to the White House many, many times. He first arrived on March 5, 2009 and visited 12 more times until his last visit on June 17, 2011. But Kindler has been active in politics for a while, I believe. (What was he doing at the White House after he was let go from Pfizer in December 2010? Who knows?) John Lechleiter, the CEO of Lilly has been to 1600 Pennsylvania Avenue a few times himself, although not nearly as many as Kindler. Lechleiter seems to hold the title for most prominent holder of a Ph.D. in chemistry (and most prominent process chemist!) to be invited to the White House. Merck CEO Ken Frazier, by contrast, seems to have been at the White House only once.

American Chemical Society CEO Madeleine Jacobs has been to the White House 8 times, with 3 of them being meetings with their relevant policy professionals. White House staffer Victoria Espinel (the "copyright czar") seems to show up in these logs on a regular basis. Once, she was in the room at the same time as Robert Massie, the president of CAS. For fans of C&EN, I'm disappointed to note that Rudy Baum hasn't appeared to have been to the White House.

Finally, our #chemjobs fibber Andrew Liveris (and his wife Paula) seem to be frequent visitors to the occupants of the White House with 19 visits. (See update 2) It gives me cold comfort that the two people in my little database search to have been at the White House are 1) the person who's laid off many, many chemists in his time and 2) the person who keeps telling the mainstream media how the country has a desperate shortage of chemical professionals.

Readers, try your hand out at the database and tell us in the comments who's been to the White House (use the "advanced search" feature.)

UPDATE: Lisa Jarvis of C&EN notes that Harvard's George Whitesides spends a lot of time (more than Liveris or Kindler!) at the White House.

UPDATE 2: An astute reader points out that Andrew Liveris is co-chair of the President's Advanced Manufacturing policy committee, and would be expected to visit the White House frequently.

*[I should take a moment and say that, within reason, there should be high levels of transparency for the behavior of elected officials. I don't really see this as a Democratic/Republican issue; I see this as a "those who have influence" versus "those who do not" issue.]

June 4 is Lab PPE Day

It's the start of the summer student season right about now, and I think it would be great to get them into the habit of wearing PPE in the lab. Wouldn't it be great if we could show everyone that PPE is a normal happy part of your day? (i.e. positive peer pressure)

So I'm declaring June 4 to be Lab PPE Day. I request that people who are interested send pictures of themselves in lab PPE to LabPPEDay -at- gmail/dot/com. On June 4 (and a little bit earlier), those pictures will be posted on the official Lab PPE Day tumblr. 

If you wear your PPE and you consider it a smart, effective way to stay safe in the lab, would you send me a picture? If you don't want to show your face, creative means of showing that you wear your PPE would be acceptable too. 

So June 4, 2012 is Inaugural Lab PPE Day. Many happy returns!

Gluts happen to other fields, too

From an astute reader, a terribly interesting article/story from public radio's Marketplace on a little bit of a looming issue for pharmacists:

Within the labor market, there's a lag effect as well. Industries and occupations that have job openings today might not have those same openings in a couple of years. 

Exhibit A for our purposes today is the professional pharmacist. Just five years ago, a pharmacy degree was a near guarantee of permanent and well-paid employment. So much so that a lot of universities started their own schools of pharmacy. In Tennessee, they went from one pharmacy school to half a dozen.  

Phil Johnston is the pharmacy dean at Belmont [University, in Nashville, TN]. He admits the agencies that oversee course work worried there might not be enough local drug stores and hospitals to support so many schools. Pharmacists have also been concerned that a glut of graduates may undercut their pay. [snip] 

...The pharmacy industry realizes it's hard for students like Deason to find jobs. The American Society of Health System Pharmacists recently authored a report. It's titled -- "Expansion of Pharmacy Education: Time for Reconsideration." Douglas Scheckelhoff is a vice president of the pharmacist group. [He said: When you almost double the number of graduates over the course of 8-10 years, over time that doubling of the graduates is going to have an impact."

Hey! That sounds pretty familiar!

[The comments are awesome, too; a person who seems to be a long-time health services person writes in to tell young graduates "hey, older pharmacists have had hard times, too" and "you don't have to work at a pharmacy if you have a pharmacy degree..." Hey, we've heard a version of that, too...]

Daily Pump Trap: 5/24/12 edition

Good morning! Between May 22 and May 23, there were 27 new positions posted on the ACS Careers website. Of these, 5 (19%) are academically connected and 12 (44%) are from Kelly Scientific Resources.

Tarrytown, NY: BASF would like to hire a B.S./M.S. chemist to perform elemental analyses. Experience with
instrumental methods such as XRF, GFAA, FAA, ICP-OES and physical property measurement such as surface area, zeta potential, color measurement and surface tension/contact angle are also desired. (I'm amused that "financial accountability" before any comments about lab safety. Oh, well.)

Thousand Oaks, CA: Amgen is looking for a Principal Scientist to be a subject matter expert for the selection of raw materials for pharmaceutical manufacture. 10 years of experience desired, as well as "[e]xtensive knowledge of the manufacturing processes of raw materials, their usage, regulatory/compendial requirements, practices, physical/chemical properties and compatibility with proteins, and risks associated with the raw materials for pharmaceutical and biological products is desirable, along with the ability to assess the impact of changes in materials or manufacturing processes."

I found the educational requirements quite egalitarian: "Doctorate degree & 2 years of directly related experience OR master’s degree & 6 years of directly related experience OR bachelor’s degree & 8 years of directly related experience OR associate’s degree & 10 years of directly related experience OR high school diploma / GED & 12 years of directly related experience."

Feel like fracking?: Unimin Corporation (Spruce Pine, NC) is looking for a B.S./M.S. chemist to work on the development of proppants (an additive to help with hydraulic fracturing, looks like.) Lab scale to pilot plant scale up and product development is a part of this position; "recent graduates will be considered."

Wilmington, OH: TimberTech is a company that develops wood products for decking, railing and fencing. They're looking for 2 positions, a senior analytical chemist (B.S./M.S./Ph.D., 3 years of industrial experience desired) and a formulations chemist (M.S./Ph.D., 3+ years experience.)

Smokin'!: The Kentucky Tobacco R&D Center would like to hire a Ph.D. analytical chemist with 3 years experience in analyzing tobacco products. This position is the "reference cigarette" program and will also be involved in developing tobacco products for FDA approval. Smoke chemistry experience desired. 

Compression saddles

A list of small, useful things (links):

• I've finally (finally!) submitted my post on fluoroacetate for Matt Hartings' toxic blog carnival. 
• You should really check out all the other entries at Matt's blog, ScienceGeist.
• David , like most medicinal chemists (it seems) looks askance at NCATS. 
• Paul Hodges: DOOOOOOOOOOOOOOM!
• Dr. Freddy is back! A neat little chemical puzzle and a complaint about BHT. 
• Lisa Balbes talks about working from home.
• The Curious Wavefunction on physics' PR problems. 
• See Arr Oh on some hot flamin' rocks. 
• I like this molecular Craigslist idea -- I think it might work, and hopefully not get spammed by unscrupulous vendors. 
• John rings in with a couple of great posts: a monomer he doesn't want to work with, and his thoughts on the Nylon-12 shortage. 

Did I miss anything? Let me know in the comments!

Process Wednesday: directionality of agitators can be important!

In passing recently, I heard that it might matter which direction (clockwise/counter-clockwise) an agitator was stirring in a reactor. I was a little surprised by this, but looking through the Handbook of Industrial Mixing, I see that it indeed matters (emphasis mine):

In addition to suspending solids off the tank bottom, a process may require homogenous suspension throughout the bulk. An additional axial flow impeller, perhaps an up-pumping one, may be needed at a higher level for this purpose... 

When using axial flow impellers, the mixer rotation can be reversed to create up-pumping action. This pumping mode can be effective for some systems, such as entrainment of floating solids and gas dispersion. The up-pumping flow provides an effective mechanism for incorporating lighter solids on the liquid surface near the wall. This avoids the need for creating a vortex, which can cause air entrainment and mechanical vibrations (see Chapter 10). For gas dispersion, the up-pumping impeller is generally used at the bottom along with a down-pumping impeller at the top. Such a configuration can provide good gas-holding capacity and prevent mechanical vibrations caused by opposite flows resulting from a down-pumping impeller at the bottom. 

So apparently there's "up-pumping" and "down-pumping" (parallel to the agitator shaft, I assume) and depending on the relative density of things inside your reactor (gases, solids, liquids, etc.), you might want to do either one. Worth remembering, I suppose.

#ToxicCarnival: Fluoroacetate

Credit: Wikipedia

I don't really have a favorite element, but if I had to choose one, I'd choose fluorine. It's such an interesting atom, especially combined with carbon. Its small size and strong electronegativity provide polymer chemists with interesting physical properties; the strong bond with carbon allows medicinal chemists the ability to block metabolic oxidation and keep their drug compounds in circulation just a little longer.

When Matt Hartings asked for bloggers to write about their favorite toxic compounds, I couldn't help but think of one of the first things I learned about fluorine and fluoroacetic acid. What happens when fluoroacetic acid (oh-so-similar to acetic acid in size) enters the citric acid cycle in place of acetic acid and is converted to fluorocitric acid? 

It is quite interesting to note that citrate synthase stereospecifically constructs (2R, 3R)-4 (fluorocitric acid) out of four possible diastereomers and, in spite of the extremely poisonous nature of this isomer, causing convulsions and ventricular fibrillation, the three other stereoisomers are not toxic. Thus, this is expressed as the "lethal synthesis" by citrate synthase.

Lethal synthesis! As you can imagine, this really struck me -- what a phrase! It was just a remarkable thing to learn, reading page 2 of a book on fluorine chemistry (the source of the above quote.)

Fluoroacetic acid (or its sodium salt, sodium fluoroacetate), one notes, is quite the poison. It's naturally occuring in a number of rather toxic plants in Africa, Asia and Australia. It's apparently toxic to just about everything (probably because just about everything has the citric acid cycle.) It's used to kill coyotes and (perhaps unsurprisingly) rodents.

Credit: Cox et al. J. Med. Chem. 2008, 51, 4239–4252

The ability of fluoroacetate to kill rodents brings us to our last story. The last thing that I really enjoy about fluoroacetic acid is how it popped up as an interesting little side note in a 2008 J. Med. Chem. paper where some Merck medicinal chemists were concerned about the acute toxicity of an anti-cancer compound with a fluoroethylpiperidine moiety. The authors explain their findings:

As part of our preclinical evaluation of 14, we studied dose proportionality in the rat with iv bolus doses of 1, 4, and 12 mg/kg. As desired, a linear increase in exposure with dose was observed, with 14 achieving AUC levels of 0.5, 2.5, and 9.5 μM h-1, respectively; however, we were surprised to find mortality within 12 h postdose in 2 of 3 rats in the 12 mg/kg group. 

Acute toxicity is not an expected mechanism-based effect for inhibition of KSP and has not been observed in our preclinical program with any compound other than 14. The dose-limiting, mechanism-based toxicity observed for KSP inhibitors both preclinically and in humans is neutropenia (depletion of white blood cells) and typically manifests in 4-10 days following compound adminstration. 

In our search for a compound-specific source of toxicity, we identified the fluoroethylamine of 14 as a potential liability. If N-dealkylation of the piperidine ring were to occur in vivo, a likely byproduct would be fluoroacetate, a known toxin with acute pharmacology. In fact, we discovered that N-dealkylated analogue 12 is the major metabolite generated in rat liver microsome and hepatocyte incubations, suggesting that formation of fluoroacetate is indeed the source of toxicity in vivo.

One imagines that Cox et al always viewed that fluoroethyl moiety with some level of apprehension and their fears were confirmed by their metabolic studies. The ability of the liver (even the rat liver!) to chew apart molecules is remarkable -- oxidizing a fluoroethyl to fluoroacetate is just another fascinating (and not entirely unexpected) example.

So for fluoroacetate's ability to reveal the inner workings of biochemistry, it's one of my favorite toxic compounds.