Chemical & Chemical Engineering News (80th Anniversary Issue), Vol. 81, No. 36, 2003, Sept. Edited by X. Lu Introduction

By a series of hypothesis-driven syntheses of novel compounds that were increasingly potent toward MEL cells, we eventually came to a compound with the acronym SAHA (suberoylanilide hydroxamic acid), with a hydrophobic group connected to a hydroxamic acid unit through a polymethylene chain. We then established that SAHA would induce other cancer cells to transform into normal cells or go into apoptosis--including the entire group of 60 human cancer cell types that are maintained for study at the National Cancer Institute. So we set out to determine the biological target of SAHA and some related compounds.

We created a radioactive photoaffinity compound based on SAHA to screen cell components, determining which ones bound the drug. At the same time, we became aware of studies by M. Yoshida in Japan concerning a natural product, trichostatin A (TSA), that also induced the differentiation of cancer cells. Yoshida had shown that TSA acted to inhibit the enzyme histone deacetylase (HDAC).

We tested our photoaffinity compound with HDAC and saw that, indeed, it was bound. Furthermore, SAHA inhibited HDAC, and the potency of our other drugs as inhibitors of HDAC ran parallel to their potency in inducing the differentiation of MEL cells. Our biological collaborators were able to clone and express the enzyme, so I suggested that they examine the purified enzyme for metals, specifically for Zn(II), using atomic absorption spectroscopy. They called back with the news that HDAC contained no metals, but I didn't believe it. SAHA, with its hydroxamic acid group, looked like a metal ligand, and the catalytic action of the enzyme HDAC looked like the kind of reaction that other zinc enzymes can perform. I received another telephone call with the news that the "purified" HDAC no longer had enzymatic activity, but that the addition of Zn(II) salts restored its activity. "Purification" had removed the zinc, and HDAC was indeed a zinc enzyme!

Our collaborator Nikola Pavletich was able to prepare crystals of SAHA bound to another HDAC and determine the structure of the enzyme/inhibitor complex by X-ray. We saw that the hydroxamic acid group was coordinated to the Zn(II) in the enzyme. Furthermore, the structure strongly supported the idea that this enzyme uses zinc in the same way that carbonic anhydrase does, binding the carbonyl oxygen of the acetyl group on lysine while delivering a bound hydroxide to the carbon of that group. Our inhibitor simply mimicked this structure.

Since that time, our consortium of chemists and biologists has been able to determine the pathway by which HDAC inhibition by SAHA causes important anticancer effects by regulating gene transcription. SAHA has been shown to be an effective anticancer agent in animal trials--and for the past three years, in human trials--against a variety of cancers. The results are very promising, and there is an excellent chance that SAHA or some related compound will prove to be an important tool in the fight against cancer. Zinc will once again turn out to be key in the biology that is central to life, as the element that permits HDAC to play its role in regulating the expression of genes.



Ronald Breslow is University Professor of Chemistry at Columbia University. He received the U.S. National Medal of Science in 1991 and the 2003 Welch Award.

ZINC AT A GLANCE Atomic mass: 65.41. Name: From the German zink, tin.

History: Ores were used in medieval times in China and India. The pure metal was isolated first in India in the 13th century, then in Europe by the German chemist Andreas Sigismund Marggraf in 1746.

Occurrence: Comprises less than 0.007% of Earth's crust.

Appearance: Bluish-white, solid metal at room temperature.

Behavior: Tarnishes in air and brittle when cast. The metal is a skin irritant; otherwise, it and most zinc compounds are nontoxic.

Uses: Mostly used for galvanizing iron, in alloys (such as brass), and in dry-cell batteries. Zinc oxide is used in photocopiers and sunscreens; its sulfide is a phosphor used in cathode ray tubes. Small amounts of zinc are essential to biological function.

CADMIUM

ROBERT L. WOLKE, WASHINGTON POST

The word "cadmium" evokes different associations in the minds of different people. I'll consider only two. The proverbial man in the street may think of rechargeable nickel-cadmium batteries. Me? I think of how cadmium got my name into the "Guinness Book of World Records."

Let's start with batteries. Every Ni-Cd battery bears the following words in fine print: "Warning: Do not dispose of in fire." Okay, so we mustn't throw them into the fireplace. But we remain haunted by the thought that our discarded batteries might wind up in an incinerator, causing unknown--but undoubtedly dire--consequences. The hoard of spent Ni-Cd batteries in the possession of people who are afraid to throw them away must be enormous.

Being sealed containers of moist chemicals, all batteries may of course explode when heated. But in addition, cadmium and its compounds are quite toxic, and an incinerated Ni-Cd battery could introduce cadmium into the environment.

The Environmental Protection Agency sets a maximum contaminant level for cadmium in drinking water of 5 ppb. And according to the U.S. Geological Survey's Minerals Information statistics for 2001, about 75% of the U.S. apparent consumption of cadmium, or a total of 2.4 million lb, went into Ni-Cd batteries. No one knows how much of this winds up in our air and water.

As consumers, we must therefore agonize about what to do with our worn-out Ni-Cd batteries, which contain about 4 g of Cd per AA size, other than throwing them in the trash and feeling guilty.

According to EPA's Toxics Release Inventory, industrial sources released 2,292 lb of cadmium into the air in 2002. To that amount, I hereby confess that I may have added 8 g in the form of the two AA batteries that I imprudently discarded. This, in spite of the fact that I live only 40 miles from Ellwood City, Pa., where the sole cadmium recycler in the U.S., the International Metals Reclamation Co., is located. Forgive me, but it was raining, and I just didn't feel like making the drive.

National efforts are under way toward the goal of making it more practical for consumers to recycle their Ni-Cd batteries--even for those who live outside of Pennsylvania.

Now on to the "Guinness Book of World Records." Cadmium consists of eight naturally occurring isotopes, including cadmium-113. Although ¹¹³Cd constitutes 12.22% of the cadmium atoms in nature, it is radioactive. Cadmium, therefore, is a radioactive element.

According to the systematics of nuclear stability, no two odd-A isobars (nuclei with the same odd mass number) having adjacent atomic numbers can both be stable; one of the pair must be unstable to -decay. In 1970, there was only one unresolved exception to this rule: ¹¹³Cd and ¹¹³In, atomic numbers 48 and 49, both of which appeared to be stable.

As soon as their atomic masses had been determined accurately enough to indicate that ¹¹³Cd must be the unstable one by an energy excess of some 300 keV, my graduate students and I decided to undertake an all-out search for radioactivity in ¹¹³Cd [J. Inorg. Nucl. Chem., 32, 2113 (1970)].

We obtained a small quantity of separated-isotope ¹¹³CdO from Oak Ridge National Laboratory, electrodeposited the metal, purified it by distillation, and counted it continuously for over 300 hours in a shielded, super-low-level radiation detector. We were able to observe the disintegration of about two atoms per hour, corresponding to a half-life of (9.3 6 1.9) X 10¹⁵ years. (I proudly point out that we nailed down that half-life within an experimental error of less than 2 million billion years!)

With a half-life of 500,000 times the age of the universe, cadmium hardly constitutes a radiation hazard. But our discovery was recorded in the 1979 "Guinness Book of World Records" as the longest lived -emitter at the time.

The record has since been broken by ⁵⁰V, with a half-life of about 4 X 10¹⁷ years. This scientific fact is ignored by today's Guinness people, however, in favor of such Earth-shaking intelligence as the speed record for opening 300 bottles of beer. (One minute, 47 seconds, if you must know, by a team of three Germans.)

Robert L. Wolke is professor emeritus of chemistry at the University of Pittsburgh and a syndicated food columnist for the Washington Post. His latest book, "What Einstein Told His Cook: Kitchen Science Explained," was a James Beard Foundation nominee for the best food reference book of 2002.

CADMIUM AT A GLANCE

Name: From the Latin cadmia, calamine (cadmium carbonite).

Atomic mass: 112.41.

History: Discovered in 1817 by German chemist Fredrich Stromeyer.

Occurrence: Obtained mostly as by-product of smelting of zinc ore, in which a cadmium-containing mineral is a significant impurity.

Appearance: Silvery metal; soft enough to cut with a knife.

Behavior: Not volatile, but toxic in humans. Poisoning rarely occurs because very little can be absorbed. Linked to kidney failure and high blood pressure.

Uses: Electroplating steel, in rechargeable (Ni-Cd) batteries, in alloys, and in some nuclear reactor control rods. Cadmium sulfide is a yellow powder that is used as a pigment. Other cadmium compounds are used in the phosphors of black and white television sets and in the blue and green phosphors in color television sets.

MERCURY