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April 18, 2002


Breaking the rules leads to faster chemical synthesis

Chemistry professor Dennis Curran has found that sidestepping one organic chemistry commandment meant finding a faster and more efficient way of creating new chemical compounds and, potentially, new drugs.

Curran presented his radical chemistry methods in a lecture, "Fluorous Mixture Synthesis Approaches to Natural Product Libraries," April 8 at the American Chemical Society's national meeting in Orlando.

Curran, Pitt Distinguished Service Professor and Bayer Professor of Chemistry, was looking for a way to speed up the process of synthesizing complex molecules when he decided to challenge an old chemical adage: Never mix pure organic compounds.

"The synthesis of complex molecules like natural products is painstaking and difficult and has always been done one at a time," said Curran. "In other words, if you want to create two, or four or eight compounds, you have to perform two, or four or eight painstaking syntheses."

The problem with mixing pure organic compounds is that it is extremely difficult to separate the ingredients completely after they have been mixed.

"We solved the separation and identification problem by introducing fluorous — highly fluorinated — tags," Curran said. "These tags allow us to reap the efficiency of mixture synthesis, making more compounds each time, yet we are still able to separate and identify the mixture components on demand."

The process involves mixing two or more compounds at the beginning of the operation, then performing only one synthesis. At the end, the researchers de-mix, or separate, the products.

"So, we get more than one product from one synthesis, and the final products are individual and pure, as if they were made by separate syntheses," Curran said.

Curran's methods work especially well for synthesizing models of active natural products or other compounds to find the best drug candidate.

"Our new mixture methods should help to discover drugs more quickly," he said. "Perhaps even more important, they could lead to better drugs, since more compounds will be tested prior to selecting a drug candidate."

Curran and his colleagues have started a Pittsburgh-based company, Fluorous Technologies, Inc., to commercialize this technique and other fluorous discoveries.


UPCI scientists present research

Researchers at the University of Pittsburgh Cancer Institute (UPCI) presented their findings at the 93rd annual meeting of the American Association for Cancer Research, held April 6-10 in San Francisco.

Highlights of the presentations included the following:

Estrogenic activity discovered in several commonly used medicinal botanicals Plant extracts often are used to relieve gynecological conditions such as menopausal symptoms as well as depression and other chronic illnesses. Although used widely, many of these remedies have not been thoroughly examined. Researchers at UPCI are studying several plant extracts to learn more about their safety, potency and hormonal properties.

In one such study, UPCI researchers found evidence that some of these extracts interact with estrogen receptors and induce strong estrogenic responses in female rats whose ovaries were removed.

"Our results indicate that some herbal remedies demonstrate measurable estrogenic activity, in spite of the fact that they are not traditionally used as such," said Patricia Eagon, associate professor of medicine at Pitt and principal investigator of the study. "This is important since it suggests that some extracts may not be appropriate for women who have a family or personal history of cancers that are linked to higher levels of estrogen, including breast and uterine cancer. While plant extracts can alleviate symptoms for a variety of conditions, women should practice caution when using them and may want to avoid their use for conditions in which estrogens are contraindicated."

Of the extracts studied, motherwort leaf, saw palmetto berry, rhodiola rosea root and red clover blossom were the most potent in terms of their estrogenic activity, and extracts of maca root, cramp bark and tumeric root were the least potent.

Critical cells in immune response found inhibited for the first time in prostate cancer Dendritic cells, as the pacemakers of the immune system, play a critical role in the primary immune response. They are the first cells to recognize antigens and to assist in the production of an immune response by helping to produce antibodies to fight disease. Pitt researchers have found that prostate cancer tumors produce factors that inhibit the growth and proliferation of dendritic cells and induce apoptosis (cell death) in dendritic cells.

"Our data may explain the strong immunological non-responsiveness that we often see in patients with advanced prostate cancer," said Michael Shurin, Pitt associate professor of pathology and associate director of clinical immunopathology. "For the first time, we have discovered that a systemic inhibition of the dendritic cells system occurs in prostate cancer."

In the study, prostate cancer tumor cells were injected into the bones of mice and had a direct effect on stem and hematopoietic precursor cells (the basic cells from which all other cells develop). The interaction between the tumor cells and the hematopoietic precursors resulted in a significant inhibition in the cells' ability to differentiate into functional dendritic cells. The study demonstrates that the generation and function of dendritic cells is significantly suppressed in prostate cancer and suggests that stimulating the growth of dendritic cells is a promising area for future research in prostate cancer therapies.

Protein found to play important role as molecular 'switch' in survival, demise of dendritic cells Pitt researchers have discovered that a protein, cdc42, plays an important role in the survival of dendritic cells in cancer. Their study showed that cdc42 was upregulated in dendritic cells treated with tumors, suppressing their activity, and that dendritic cells grew when the expression of cdc42 was decreased.

The study further demonstrated that dendritic cells treated with tumors not only expressed higher levels of cdc42, but also expressed 15-fold less of a cdc42 inhibitor (Rho-GD-1) and 5.7-fold more of a cdc42 activator (ezrin).

"The discovery of an increasing number of genes regulating dendritic cell activity and a better understanding of the molecular interactions between immune cells has provided the molecular basis for specific approaches of active immunotherapy in cancer patients," said Michael Shurin, Pitt associate professor of pathology and associate director of clinical immunopathology. "This new direction, which one could term 'therapeutic molecular immunopathology,' will allow us to identify new molecular targets in dendritic cells and to possibly design new therapeutic approaches for cancer by genetically engineering the cells to protect them from tumor-induced apoptosis. This can translate into new possibilities for the creation of highly efficient vaccines for cancer therapy."


Study shows why heart transplant patients start smoking again

Nearly half of ex-smokers who receive heart transplants resume smoking at some point after their life-saving operation, and now researchers have good evidence to suggest who is at risk of relapse.

Results of a Pitt study presented at the annual meeting and scientific sessions of the International Society for Heart and Lung Transplantation outline for the first time the strongest predictors for smoking relapse in heart transplant patients.

Leading the list: a short abstinence period before transplantation, bouts of depression or anxiety within a few months of the transplant and a caregiver who smokes.

"Understanding which patients go back to smoking should help us design more effective intervention strategies to aggressively target high-risk patients as well as their caregivers," reported Carol Stilley, an assistant professor of nursing and psychiatry at Pitt's schools of nursing and medicine.

"Among the general population, about 90 percent of those who try to quit will relapse within a year, so in many ways our transplant patients are showing much greater willpower. Yet the detrimental effects of smoking depend on how much and for how long someone smoked, and in an immunosuppressed patient, these detrimental effects are likely to be much greater," said Mary Amanda Dew, professor of psychiatry, psychology and epidemiology, and the study's director.

Drugs that transplant patients take to prevent organ rejection suppress their immune systems, making these patients more susceptible to infections and cancers. A smoking history and relapse to smoking could compound cancer risks for transplant patients. In recent years, transplant teams have seen more of their heart transplant patients develop inoperable lung tumors — all previous smokers — four to five years after their transplants. Smoking reduces survival.

Studies conducted in Europe have indicated a 37 percent five-year survival rate for heart transplant patients who smoke, compared to an 80 percent survival for their nonsmoking counterparts.

The Pitt researchers studied 202 heart transplant recipients for up to three years. Of these, 144 (71 percent) had a history of smoking, from two to more than 95 pack years, a calculation based on the number of packs per day times the number of years smoked.

As part of a longitudinal study about health habits following transplantation, the researchers conducted in-depth interviews with the patients, their family caregivers and the patients' transplant nurse coordinators at two, seven, 12 and 36 months after transplantation.

Fifty-five recipients (27 percent of the sample of 202 participants) started smoking at some point after their transplant, and of these recipients, 45 (82 percent) started smoking within the first year, including 26 (58 percent) who started within two months. One patient who had not previously been a smoker took up smoking an occasional cigar. Throughout the three-year period, 25 smoked 10 or fewer cigarettes a day, nine smoked between 11 and 19 a day, and four smoked a pack or more daily. The amount was unknown for the remaining 11 who were mostly cigar smokers.

Based on the series of interviews, researchers also were able to perform statistical analyses indicating the strongest predictors to smoking relapse. Patients who quit smoking for a period of less than six months before their transplant (as opposed to those who quit for longer periods of time) were much more likely to start smoking earlier and more often. Depression and anxiety within two months after the transplant also made it more likely that relapse would occur early, and these patients reported smoking the most — more than a half a pack a day.

Having a caregiver who smokes was less significant but remained a strong predictor, say the researchers. Of 194 caregivers who took part in the study, 50 were smokers. Of the 55 recipients who smoked, 21 had a smoking caregiver.

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