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Boosting the Pipelines: Mother Nature’s Resources
Oct. 22, 2008 | Legend has it that vil agers in northern Greece used to walk their old, ailing (read: no longer useful) donkeys up a mountain and leave them there, tied to a yew tree. The poor starving beasts would resort to eating the tree’s leaves and bark – and die. Women cal ed it, simply, the “donkey tree”; men were more apt to refer to it as the “mother-in-law tree.” In his book Gal ic Wars, Caesar also described how, after being roundly defeated by the Roman legions, the barbarian chieftain Catulvolcus committed suicide by drinking tea made from a yew tree extract. These days, we’re more likely to associate this tree with paclitaxel (Taxol), one of the bigger anticancer drug success stories. But there were clues even from ancient times, says K.C. Nicolaou, a world-renowned synthetic chemist at San Diego’s Scripps Research Institute, whose group, incidental y, was the first to publish a completed synthesis of paclitaxel in 1994. “People in ancient Egypt and Greece knew that chewing bark from the wil ow tree would relieve fevers and pain, but only when chemistry came of age were scientists able to isolate and modify the active ingredient, producing Aspirin,” Cyprus-born Nicolaou says, by way of another anecdote. He’s a passionate believer in utilizing much more of what nature has to offer, for drug discovery. Natural products provide excel ent drug leads, he says, because most have evolved to bind to biological receptors as part of the living world, and are thus likely to exert interesting biological properties that could be disease-relevant. In fact, over 60 percent of today’s drugs originate, one way or another, from nature. Nature’s molecular secrets are most often found in the soil, forests, and the ocean, Nicolaou explains, and some of these have been particularly successful against infectious disease and cancer. After al , since microbes literal y wage chemical warfare among themselves for territory and food, they provide a great source for antibiotics such as penicil in and vancomycin. We can also thank a certain fungus for the substance compactin, from which cholesterol-lowering statins such as Merck’s Mevacor and Pfizer’s Lipitor were eventual y derived. Taxol aside, other valuable cancer agents can be developed from plant and marine self-defense toxins. Yondelis (ecteinascidin), for instance, was developed by PharmaMar (a subsidiary of the Zeltia Group) and recently received European approval as a new chemotherapy against advanced soft tissue sarcoma; its active ingredient was isolated from sea squirts.
“Diabolical” syntheses
In Nicolaou’s laboratory, the focus is on chemical y synthesizing such complex and biological y active natural products. “We’re very proactive; we see
what’s out in the literature from the people who isolate these products, and when we read about novel ones with interesting biological activities, we immediately begin synthesizing them in the lab,” he says. Many of these molecules are often too scarce, upon harvest, to al ow for thorough biological investigation, hence the need for chemical synthesis. More importantly, he adds, having a synthetic route to these molecules makes it possible to design analogs, which are often a source for superior drug candidates. Nicolaou has a pretty impressive resume of syntheses, many tackled with what others have cal ed his Greek heroic spirit, despite possessing structures described as diabolical, bizarre, or synthetic nightmares. Calicheamicin, an anticancer antibiotic of bacterial origin, was among his first chal enges.
Brevetoxin B – from the “red tides” of algal blooms – is perhaps the one for which he’s best known, a tortuous piece of work that took 12 years and 82 steps. He’s also synthesized Pfizer’s cholesterol-lowering and anticancer CP molecules, which were isolated from a fungus. As wel , Bristol-Myers Squibb’s Ixempra, shown to be effective against Taxol-unresponsive breast cancers, hails from the epothilones, first discovered in soil bacteria col ected from the banks of southern Africa’s Zambezi River, and subsequently synthesized by Nicolaou’s group. They’ve since made “hundreds” of epothilone analogs, many of which have been licensed by companies like Novartis and Abraxis. Currently, Nicolaou is searching for a superior molecular version of platensimycin, reported by Merck scientists in 2006, and which Nicolaou’s group was the first to synthesize. In typical pharma fashion, the folks at Merck are “keeping their cards very close to their chest; we don’t know what they’re up to,” Nicolaou says. What he does know is that platensimycin has, thus far, proven to be a highly potent antibiotic, wiping out al drug-resistant bacteria in its path. Nonetheless, Nicolaou suspects its current form may not be the optimal drug as it lacks oral activity; he’s thus looking to change its structure, stabilizing it in the bloodstream. “We haven’t discovered the magic compound yet, but we’re working on it,” he says.
At any one time, there could be as many as a dozen different compounds being synthesized in the Nicolaou lab. The trickier the compound, the more likely he is to claim it as a chal enge. “I look at a molecule, fal in love with it, and decide to synthesize it,” he says, his Hel enic cultural heritage coming to the fore as he describes the personal significance of a molecule’s physical attraction. And, as seen with brevetoxin B, it can sometimes be a beastly business, one which Nicolaou likens to a war – “you have to fight to get the target molecule, and your opponent, in a way, is Nature herself.” What it boils down to is a combination of good planning and the ability to cope with frequent strategy redesign, along with a large dose of creative thinking – often, he says, in the wee hours of the morning. A true academic, he keeps a notepad next to his bed for just such flashes of inspiration.
Have patience, will succeed
Nicolaou urges pharmaceutical companies to make more and better use of this “natural products pathway,” even if it requires a fair bit of time and
money. “I believe in systematic drug discovery, which takes patience,” he remarks. “Our pipelines have become very thin, and people are unhappy about it. Twenty years ago, scientists were promising that ‘we’re going to decipher the human genome, and then we’l have medicines for every disease.’ What’s happened in the meantime? Big Pharma started de-emphasizing natural drug discovery – I think we became too impatient; we were asking for miracles, to discover drugs in a year or two when that’s just not possible.” Being an academic, Nicolaou owns that his perspective is probably different, without the pressure of needing to “discover a new drug each year.” But he believes investing both money and patience in basic research wil eventual y yield good fruit, expanding the modern medicine cabinet. Also, given the tremendous advances in al things “omics,” the list of biological targets against which newfound natural products can be screened just keeps growing.
“God knows what they’l find – probably many active compounds, enzyme inhibitors, agonists and antagonists,” he says. This wil lessen the need for searching combinatorial libraries, for where natural products often come with high potencies, the same is not necessarily true of library compounds, which may also have little to no activity. “If we can combine al these advances in biology with those in chemistry, we’l have tremendous power for direct drug discovery,” Nicolaou says.
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