The Salk Institute and Sanford Burnham Prebys license ULK1/2 inhibitors to Endeavor BioMedicines for treatment of cancer

The Salk Institute and Sanford Burnham Prebys license ULK1/2 inhibitors to Endeavor BioMedicines for treatment of cancerment-of-cancer/

Happy to see that the compounds that we developed at SBP in the Cosford lab and in conjunction with the Shaw lab at Salk are being advanced further into preclinical development and then hopefully on to the clinic to help in the treatment of patients!

Half-Page Review: Allyl Carbamates by the Aza-Ene Reaction

Originally reported in: "ALLYLCARBAMATES BY THE AZA-ENE REACTION: METHYL N-(2-METHYL-2-BUTENYL)CARBAMATE" Org. Synth. 1987, 65, 159.
http://orgsyn.org/demo.aspx?prep=CV8P0427

Continuous Flow Reaction Setup

Here's a reaction that I set up awhile back in which I reacted a chloropyrimidine with an aniline to obtain the substitution product. The general reaction scheme is shown below. In this reaction acetonitrile is the solvent and the temperature in the reactor is 160 degrees Celsius, much higher than you could obtain in traditional flask-based chemistry where you're limited by acetonitrile's boiling point of 82 (unless you go sealed tube).

We sometimes use flow chemistry instruments to carry out our reactions in lab, and in this particular case I wanted to share because the experimental setup was unique and interesting (even if I'm biased to say so!). I explain it mostly in the video.

In general, most flow chemistry experiments are set up to dispense the product into a vial or bottle after exiting the reactor. In this case, I wanted to prolong the amount of reaction time and was limited in the number of coiled tube reactors that we have, so I hacked the setup to make it a continuous loop. That way I get the benefits of working in flow (increased temperatures and pressures) and I'm not constrained by residence time within the reactor.

Here's a link to the type of flow chemistry instrument that I used in this experiment: https://www.vapourtec.com/products/r-series-flow-chemistry-system-overview/.

Academic Lineage

It's a common desire to want to know your ancestry, or where you come from. Many have mapped out their family tree and there exists a plethora of sites on the web to aid in one's endeavor. That said, I imagine few people have taken the time to map out their academic lineage. For those who've completed some amount of postgraduate education and work, fortunately there's a website that allows the user to do just that.

There are a few options out there, but one that I like is academictree.org. It's a simple interface and though I'm only interested in chemistry (well, I'm interested in many things, but for the sake of academic genealogy), they keep a database of a number of academic fields. If you find that you or someone you're not looking for isn't in the tree yet, it's easy to make additions. So, all you chemists out there--fill out that tree!

Taking a look at my lineage, you can see that I'm only 3 generations removed from one and only Robert Woodward. I'd like to think that my analytical and chemistry skills are in some way influenced by R.B.W.'s impact on my academic forebears. My Ph.D. advisor, Yoshi Kobayashi, certainly was strongly influenced by his Ph.D. advisor, Tohru Fukuyama, and instilled a similar work ethic in us, his graduate students. Yoshi also spent time as a postdoc in Yoshito Kishi's lab at Harvard, so really, my chemistry training has a sort of "East meets West" flavor to it.

Link to my tree

Our new paper describes drug with potential for new anticancer strategy

I just wanted to use this post to give a little shameless promotion to the work published by the Shaw and Cosford labs (that includes me!) last week. I've put links below to the press it received as well as to the article itself.

The work we published sheds more light on the autophagy process and its relevance to cancer therapy. Specifically, our labs have helped to advance the understanding of a hot new target, ULK1, that is crucial to autophagy. We show in the paper that induction of autophagy by nutrient limitation (similar to the tumor microenvironment of a cancer) or by an mTOR inhibitor combined with inhibition of ULK1 by SBI-0206965 causes cell death. Basically what's happening is we're activating a pathway and preventing it from proceeding further downstream, and the response by the cell is death.

Other labs have very recently released their findings regarding their own ULK1 inhibitors. However, the key difference that sets our compound apart is its selectivity. It turns out our compound, "6965", is amazingly selective. Anyone who's been involved in the development of kinase inhibitors knows that kinase selectivity can be difficult to achieve. The reason being that most small molecules are ATP competitive, and therefore bind to the ATP binding site, a well-conserved region of the enzyme. One example of a highly selective drug used in the clinic to treat breast cancer is the tyrosine kinase inhibitor lapatinib, which is also ATP competitive.

When designing a drug, you generally want that compound to be very specific for the molecular target; whether it be a receptor, kinase, or some other biomolecular target. Off-target effects can often give rise to toxicity from a clinical perspective.

Selectivity is perhaps even more important for biologists using a tool compound to study a biological pathway. Any off-target interactions can cause ripple effects on a number of closely related pathways and even feed back into the pathway the biologist is studying, making analysis very difficult or impossible.

We've synthesized and tested a substantial library of compounds so far, so more publications will follow to detail our discoveries in this developing, but very important field of chemical biology. So stay tuned!

Salk press release
UT San Diego article
Genetic Engineering & Biotechnology News
Molecular Cell article

Crystals and Chemistry

For some compounds, obtaining crystals can be quite difficult. Of course, it always seems to be the most difficult for those particular compounds for which you need crystals. For example, when chemists want absolute and definitive structure confirmation, X-ray crystallography is the de facto standard. But the crystallographer needs a good quality crystal to run the experiment that will determine the molecular structure. This particular compound is one for which I don't need X-ray data for--I'm certain of its structure; thus why it crystallized so easily!

It's hard to capture the beauty of the crystal with a camera (or at least it is for me, given my nonexistent photography skills), but I wanted to share what I thought was a pretty cool looking pattern of concentric rhombuses (diamonds).

Half Page Review: 1,2-anti-Diamine Synthesis - Sulfur Diimides

Originally reported in:

"Attempted synthesis of biotin". J. Org. Chem., 1988, 53 (5), 1116–1118.

http://pubs.acs.org/doi/abs/10.1021/jo00240a043

As Pure As the Driven Snow (A Random Musing on the Color of a Chemical Compound)

Yesterday I ran a reaction that behaved beautifully. It's a reaction where I've optimized the conditions to make the process nicely efficient, and now that that groundwork has been laid, all that I have to do is plug various electrophiles and nucleophiles in and it tends to work without a hitch.

I conduct the reaction under microwave irradiation, and the process is similar to how you cook or heat food at home. The microwaves excite molecules that are polar in nature (have a significant dielectric constant), causing them to gain kinetic energy and excite neighboring molecules. This manifests itself as heating your food, and in my case, heating my reaction mixture. Just as it takes a fraction of the time to cook/heat food by microwave compared to, say convectional heating, the same is true for chemical reactions in many cases.

That little bit aside, I could tell that my reaction had worked well by a quick LC-MS of the crude reaction mixture. It was clean enough that all that was necessary was to add the proper solvent (in this case I found acetone to work), which preferentially dissolved the impurities and not the product, and then filter the solid.

What I got was a satisfyingly white powder. Organic compounds typically tend to be some shade of white, so this isn't an uncommon occurrence. And sure, color isn't the best indicator of compound purity. But on some levels it might be the most satisfying (especially when you realize you don't have to run column chromatography).

A little chemistry tangent: inorganic molecules often take on more vibrant colors due to the ease with which electrons within those molecules can be excited or promoted to a higher energy level by light. Light (or a photon) is absorbed by the molecule to excite the electron, and the energy of the photon must match the energy the electron needs to reach that excited state. As you might know, the color of light is determined by its wavelength and is correlated with its energy. Thus, a molecule that absorbs red photons (λ=700 nm, lower energy light) will appear green, and a molecule that absorbs violet photons (λ=400 nm, higher energy light) will appear yellow. It's no surprise that if you look at a color wheel, you'll notice a trend. Organic molecules tend to be white because they don't absorb light in the visible region. The lowest unoccupied molecular orbitals (LUMOs) for organic molecules tend to be of higher energy and require ultraviolet light for promotion of electrons--thus their white color (all colors of the rainbow reflected).

Now, of course, afterwards I use the requisite analytical techniques to truly verify purity; namely, liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance (1H-NMR). But when one sees the off-white heterogeneous crude reaction mixture become a nice, white powder in the filter funnel, one honestly has a good idea what they're going to see when the full and proper analytical workup is given.

Grant writing

Greetings fellow science enthusiasts and Organic Matter followers. Just wanted to write a quick note to apologize for not posting a new entry this week. I've researched and written part of it, but had to put it on hold to finish up some grant writing that's at the top of my priority list for the week. It's an R01 grant and I've got responsibility for the chemistry section. I have some really nice ideas for chemistry to use, so a lot of my writing opportunities are being taken up by that right now. I promise to finish up and post the next entry very soon! Enjoy the Memorial day weekend everyone!

:-)

(±)-Thujopsene

For my inaugural blog post, I thought I'd take a look at an oldie, but a goodie–a (semi?) total synthesis from the groovy 1960s, that of racemic thujopsene. This one comes to you courtesy of the now-deceased Prof. William G. Dauben (a fellow original Ohioan like myself) and crew from the University of California at Berkeley. I like to look back at classic synthesis papers not because I'm old (I'm 32, I'm not that old yet!), but because they often contain instructional chemistry that's no longer utilized but still very useful. Thujopsene is a sesquiterpene that really has little bioactivity to speak of. Being one of the essential oils of some conifer trees, it does have a nice scent, though.

I put the semi part in there because it's not clear what the origin of their octalin starting material 1 is. Either way, their first reported step provides a nice contrast between reaction kinetics and thermodynamics. Enolate formation* from 1 with tert-butoxide and addition of iodomethane to 2 provides the less thermodynamically stable alkene in dimethylated 3 (the alkene conjugated with the ketone takes that title). Dimethylation at the a-position leads to the kinetic product. A little redox manipulation followed; Wolff-Kishner reduction (a reaction analagous to the Shapiro reaction) of ketone 3 followed by allylic oxidation to the ketone 5 with Cr(VI). The mechanism of allylic oxidation with chromium is said to proceed via allylic hydride abstraction, followed by trapping of the allylic cation by the reduced chromium reagent.

The powerful reducing agent lithium aluminum hydride was utilized to accomplish a diastereoselective 1,2-reduction of the enone 5 from the convex face to give allylic alcohol 6 in a 95:5 d.r. The authors also attempted Meerwein-Ponndorf reduction of the enone using Al(Oi-Pr)₃. However, nearly a 1:1 ratio of stereoisomers was obtained in this case (58:42). Honestly, given the choice of reducing agent, it's surprising the molecule wasn't completely reduced, alkene and ketone. Nowadays, the Luche reduction is commonly employed when one wants to selectively 1,2-reduce an enone, and this method makes use of the much less reactive sodium borohydride.

The next step was essentially the crux of the paper, as they mentioned in the opening paragraphs their recent studies on cyclopropanation of allylic alcohols (JACS, 1963, 86, 468). Specifically, they found that cis-selectivity was observed, a fact that is crucial to the stereochemistry obtained in the conversion of 6 to cyclopropyl-containing 7. Thus, usage of the Simmons-Smith organozinc reagent gave 7 as a single isomer, but in relatively low yield. A look at the experimental section shows that quite a bit of work was necessary to get the fully purified material, including a spinning band column distillation, recrystallization and flash chromatography over alumina.

Jones oxidation of the hydroxyl group in 7 gave 8 in expectedly high yield, and addition of MeMgBr followed by a workup with ammonium chloride resulted in facile dehydration to alkene 9, with intermediate alcohol 8 not being isolated. The authors mention that a characteristic reaction of thujopsene (9) is its rearrangement to the ring-expanded widdrol (10), and that was accomplished by treatment with oxalic acid in wet ethanol as a final proof of synthesis.

Overall it’s a nice synthesis. Typically when an organic chemist sees a decalin ring structure with a distal alkene, they immediately think of employing a Diels-Alder reaction. However, the presence of the cyclopropyl group necessitates a slightly different synthetic plan. The cyclopropanation reaction wasn’t quite as efficient as in their less complicated model systems, but still delivered the product stereospecifically. Perhaps some of the newer cyclopropanation reagents (rhodium carbenoids, newer organozincs) could give better yields.

*For a half-page review of stereoselectivity in the reductive alkylation of bicyclic enones, see this half-page review I made back in my grad school days.

Original article: Dauben, W. G.; Ashcraft, A. C J. Am. Chem. Soc. 1963, 85, 3673. http://dx.doi.org/10.1021/ja00905a032