Radical Synthesis of Natural Substances

Chemists have had a difficult time synthetically creating many important natural substances in the laboratory.

Bioactive compounds found in marine and terrestrial organisms often have anti-cancer, anti-bacterial and other desireable qualities. The cost of synthesizing the compounds can be prohibitive, though.

This is a critical concern, as identification of a reasonably economic means of production for marine and other natural products is typically one of the most challenging hurdles in a potential drug's commercial development. An overly complex and expensive synthesis can even slow or halt the development of an otherwise promising drug candidate.

....A range of drugs from aspirin to the widely used cancer treatment Taxol has been discovered in nature, but the complexity of producing natural products has made some companies reluctant to focus on them.

“There is this far-ranging and damaging perception that natural products are too complex to be used in a drug discovery setting despite their overwhelming track record in medicine,” says Baran. “I think if our work has helped in even a small way to revive the use of natural products, then we've served our purpose.”

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Phil Baran and colleagues at Scripps Institute have opened the door to faster and more economical synthesis of natural products by changing the rules.

A radically different approach to constructing complex molecules could help to tap the pharmaceutical potential of natural products. The concept, devised by Phil Baran and colleagues at Scripps Institute, La Jolla, California, promises to generate natural products in much larger amounts than conventional methods, making biological testing much easier for drug discovery scientists.

Most total syntheses, which assemble complicated carbon-based molecules from relatively simple building blocks, make liberal use of protecting groups. These chemical shields prevent completed parts of a molecule being altered while chemists are still tinkering with other sections that are still under construction. However, adding and removing protecting groups can add many steps to a synthesis, cutting overall yields drastically.

Baran's team have now made a collection of marine natural products without using a single protecting group. Instead, they take advantage of the intrinsic reactivity of the molecule's different functional groups.

This unconventional approach delivered several grams of compounds such as ambiguine and welwitindolinone in less than 10 steps. What's more, the reactions were enatioselective - they made only the preferred mirror-image form, or enantiomer, of the molecule, instead of a racemic mixture containing equal amounts of both enantiomers. This is a vast improvement over traditional syntheses, which make milligrams of racemic product in around 30 steps.

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Hat tip Biosingularity blog. Biosingularity blog specifically tracks developments on the cutting edge of biology, and is worth a regular look.

Stupidity Kills----Part I: Malaria

Malaria is a major killer of children under the age of five. Perhaps a million children die of malaria every year. A million children a year. How is that possible? Who would allow such a thing to continue to happen, year after year?

Most malaria deaths occur in impoverished nations of sub-saharan Africa and Asia, and large organisations have been spending billions of dollars a year to try to reduce the impact of malaria--particularly devastating on young children, and pregnant women. The World Health Organization has appointed "an Iron Fist" to administer its world anti-malaria program.

Dr. Kochi, who in the past ran the agency's Stop TB initiative, has never been known for his diplomatic skills. A 57-year-old graduate of Japanese medical schools and the Harvard School of Public Health, he ruled the Stop TB campaign with an iron fist, colleagues say, and by his own admission, so alienated the Rockefeller Foundation and other partners that he was ultimately forced out of the job.

But even his critics admit that he was a decisive strategist and that the tuberculosis campaign was one of most effective the W.H.O. has run.

"His tactic really worked," said Dr. Jacob Kumaresan, a former chief of the Stop TB Partnership in Geneva and now the president of the International Trachoma Initiative. "With his staff, he's pretty strict — those who don't produce results will be laid off. But he's very bold, and I think he's on the right track." Read more at the source.

Sounds hopeful, right? Dr. Kochi appears competent, from the article, but the apparatus he has to work with is not. From the WHO infrastructure, to the unscrupulous third world drug manufacturers, to the homicidally corrupt governments through which Kochi must work to reach the people who are sick, the situation is anything but hopeful.

But people like to blame those who try to help, more than they like to face the bottom line problem that is killing people. Here is an example of that "blaming the helper" attitude from a Lancet article:

8 years ago, the World Bank launched the Roll Back Malaria campaign, promising to halve malaria deaths this decade. After studying its options, the Bank made an unprecedented pledge before Africa's heads of state in 2000: it would spend (or rather, loan) $300–500 million to fight malaria in Africa.2 This promise of funding was warmly welcomed, because contemporary economic arguments held that malaria cost Africa dearly—perhaps even tens of billions of dollars a year. But the Bank failed to lend Africa the funds for malaria control that it said it would, and rather than admit this with candor, the Bank concealed the fact by using untransparent and contradictory accounting.

In 2001, the year after its pledge to Africa's heads of state, the Bank made the impressive claim that it had “about $450 million out in various forms of anti-malaria programs”.3 But by 2002, it appeared to backtrack, writing that “Bank direct financing for malaria control activities is over US$200 million”.4 The Bank also cut the number of countries where it supported antimalaria programmes, from 46 to about 25.3,4 Although the Bank's statements lack complete precision, they do give the appearance that in just 1 year, the Bank slashed a quarter of a billion dollars of malaria-control funding, and nearly halved the number of countries it assisted. And so on.

Naturally, the World Bank is corrupt due to bureaucratic rather than meritocratic staffing methods. But why not admit the real bottleneck? Why not face up to the problem that refuses to be solved--corrupt governments from the national to the regional level?

Here is a harsh bucket of cold water reality to the face:

But journalist June Arunga doesn't think this [foreign aid] will really help in the long run.

....Arunga grew up in Kenya, and she wonders why Americans waste money on foreign aid to Africa … when many politicians just steal it.

"Africa is full of governments that steal money," she said.

Billions of dollars are hidden by African politicians in Swiss banks or spent on mansions, lavish trips and luxury cars.

Even food aid gets stolen. When "20/20" went to Kenya a few weeks ago, Kenyan farmers said bags of food aid from their government never arrived.

"You find most of it is getting lost on the way," farmer Joseph Nthome said. Lost, but then found … for sale in street markets.

So much is stolen because we rely primarily on governments to administer foreign aid, and many African governments are kleptocracies.


Here are some harsh facts about malaria:

# Forty-one percent of the world's population live in areas where malaria is transmitted (e.g., parts of Africa, Asia, the Middle East, Central and South America, Hispaniola, and Oceania).
# An estimated 700,000-2.7 million persons die of malaria each year, 75% of them African children.
# In areas of Africa with high malaria transmission, an estimated 990,000 people died of malaria in 1995 – over 2700 deaths per day, or 2 deaths per minute.
# In 2002, malaria was the fourth cause of death in children in developing countries, after perinatal conditions (conditions occurring around the time of birth), lower respiratory infections (pneumonias), and diarrheal diseases. Malaria caused 10.7% of all children's deaths in developing countries.
# In Malawi in 2001, malaria accounted for 22% of all hospital admissions, 26% of all outpatient visits, and 28% of all hospital deaths. Not all people go to hospitals when sick or having a baby, and many die at home. Thus the true numbers of death and disease caused by malaria are likely much higher.

Malaria is neither the leading cause of death world wide (#8), nor the leading cause of childhood death world wide (#4). But WHO officials know how to prevent malaria, and they know how to cure it. So what is the problem? Stupidly corrupt government leaders and officials that suck up most of the contributed aid before it gets to the people.

Stupidity kills. What is the connection between stupidity and corruption? A lot stronger than you might think.