I. INTRODUCTION

Medicinal chemistry is one of the oldest and, in a different context, one of the youngest divisions of organic chemistry. The rational design of synthetic, target-selective, malady-specific agents (e.g., Tagamet^R, Lopressor^R) has emerged in the past 25 years, yet, tribal, or herbal cures and medicines are as old as civilization itself.

Unfortunately, the old and the new have not blended as well as hoped to provide society with "trouble-free disease cures." The past two decades witnessed increased growth and interest in combining traditional/herbal medicines with modern analysis and structure manipulation to yield - effective, safe, patient-correct, profitable - medically important compounds. Note: 25% of all current prescriptions are derived from plant sources.

The purpose of this course is to provide an understanding not only of how specific drugs work but also to increase your awareness of drug discovery and the rich history of medicinal chemistry that has preceded us. The historical role of medicinal chemistry will be presented from the standpoint that it is rooted largely in herbal medicine. Once an appreciation of "nature's pharmacy" has been communicated, more "scientific" and "chemical" lectures will follow detailing foundation information needed to interpret and understand medicinally active agents. Next, specific medicinal agents will be discussed including their structure, site of action and effect. The second half of the semester will describe specific drug-receptor interactions.

Broadly speaking, three main pathways of discovery are recognized in medicinal chemistry: namely, isolating or imitating naturally occurring substances (e.g., antibiotics), chance observation and random testing (e.g., cocaine, digitalis), or setting up research to compare the fundamental nature of a biological process in health with its altered function in disease. Interestingly, two of the three methods rely more or less upon herbal knowledge and this is why we will first link "herbal science" to medicinal chemistry.

II. FOLK AND HERBAL MEDICINE - AN INTRODUCTION

Before embarking upon some history of herbal cures/remedies let's first ask some questions of medically active agents derived from plants.

• Why do molds produce antibiotics like -lactams (e.g., penicillin, cephalosporins)?
• Why do plants/molds produce lysergic acid?
• Why does foxglove produce digitalis?
• Why are certain vitamins (the ultimate medicinal agent) produced by plants and not manufactured by mammals?
• What about recent recommendations by the AMA toward (a) "roughage," (b) preventative medicine as a means toward reducing heart disease and cancer risk. Do these new directions signify an acceptance of herbal medicine or utilizing a battery of methods to reduce health risk? Consider the cost efficacy. Side effects. Approximately one-third of all hospitalization, treatments, and prescriptions are wasted costing America $160,000,000,000 annually.

 

The purpose of this section is not to convince you of the "herbal holistic approach" to medicine, but to make you aware that "pure, planned science" is not the only source of current pharmaceutical agents. Further, we have much to learn from plants/mold/yeast/fungi/etc., they have been on this earth much longer than humankind fighting to stay alive.

    A. Brief Comparisons of Western and Eastern Medical Science Approaches.

Coca leaves and cocaine: The Coca plant has numerous alkaloids present in its leaves. There is an overall stimulant effect, suppressed hunger, elevated blood pressure, etc. These observations and effects were predominantly learned from South American civilizations (mainly farm workers and coal miners). Western science looked at the plant and reasoned, "break it apart and find out what molecular component works and make it into a useful drug." Hence, cocaine, procaine, lidocaine and Novocaine were unveiled. However, chewing the leaves of the plant, the herbal approach, has very different effects than purified material when compared on an equal concentration basis. Clearly, the route of administration (oral vs. i.v. vs. nasal) alters the effect. Second, there are other components in the leaves that also alter the effect. Perhaps these "components" are antagonistic, synergistic or just complementary. Chewing coca leaves cause 70% less addiction/heart attacks/bp increases than their synthetic or purified counterparts.

Ginseng has been used for thousands of years as an anti-stress and mediator of well-being. Over 2,000 scientific papers have now addressed its utility and yet no "single molecule" has been associated with its calming effect. Does this mean it is a hoax in terms of Western medical practice? Rather, the active principle(s) may be labile to isolation, may be a combination of molecules, or may be macromolecular. We shall re-examine Ginseng a bit more closely later.

Chinese rhubarb: Some diseases treated mostly by surgery in the West are treated mostly herbally in the East. For example, acute appendicitis is treated with rhubarb (contains anthroquinones which serve as laxative and antibiotics and tannins which serve as cathartics) are used in China yielding a 90% cure rate over a three-four day period. If peritonitis occurs, antibiotics (penicillin) are employed followed by surgery as a last resort. This exemplifies the perfect combination of herbal/technological medicine. Clearly, a three-four day period in which pain can be a major issue would lead more Westerners to choose surgery. However, if you consider the cost, the surgical invasion of your body, and the resultant prophylactic drugs (antibiotics) used following surgery to prevent pain/infection, herbal medicine may not look as bad. Average hospital stay is 2.5 days (depending on age) for an appendicitis costing about four thousand dollars in the US. Cost of herbal medicine; approx. 8-10 dollars. How are the methods comparable?

Historical differences in the development of herbal medicine between Eastern and Western cultures require that the two patterns be discussed separately. Why do East (herbs, acupuncture) and West (purified drugs, surgery) practice medicine so differently?

         1. The West: Herbs were once used and studied intensively in this country. Concomitant with its development, synthetic medicines that had the "power" to wipe out certain diseases were developed. As cure after cure was found, great excitement spread through medical research. And unlike the older vanguard, which attempted to preserve botanical medicine, the younger scientists could not resist the excitement of modern drug research. Thus, the scientific method spawned a new era of medicine. Therefore, the movement away from natural and toward synthetic cures could not be considered a conscious one.

During this period of change, the notion of specificity (one disease-one site of action-one cure) evolved (e.g., smallpox, cholera, tuberculosis, typhus, etc.). Herbal medicine did not fit well into this new theme. Public attitudes also changed as a result. The "big trust" invaded American thinking:
 

• trust food specialists for guidance of adequate nutrition and foodstuffs

• trust medical specialists to prevent disease and find cures

• trust the government to ensure we are not poisoned by our environment/production/etc.

• diabetes
• cancer
• heart disease
• viruses

Today, the scientific method is a powerful, precise and directed tool sitting at the right hand of a physician (the least skilled scientist in the chain of drug applications). There are limitations - medical science in the West is a unique combination of political and economic factors. Unusual criterion are used to choose which compound to promote. Efficacy is required of course, but profitability is also a major consideration. The material must be patentable and cover R&D costs! No patent-not economically acceptable, therefore herbs, which are not patentable are less desirable. Are there enough people afflicted [globally] to make research and development a worthwhile endeavor?

Herbs are not drugs as defined by the government. The purity, quantity, etc. cannot be controlled or regulated easily. There are no patents possible, No profit possible. And a very important consideration: who is an expert of traditional herbal medicine versus who is a charlatan?

         2. The East: China, for example, accepts modern technological advances but does not abandon its folk-medicine history, learned through thousands of years of tradition, trial and error and positive results. An interesting note is that U.S. scientists have recently turned to China for a wealth of folk cures for cancer and AIDS although North America is rich in folk remedies through native American Indians. The eastern approach is to be "in tune with" and not to "control" disease. Shen-nung Pen-t'sao Ching, the first and anonymous Chinese materia medica was written over 2000 years ago! Chinese medicine depends mainly upon empirical approaches. For centuries, experimentation was done directly on patients without animal testing. As a result, thousands of Chinese herbs, plants and concoctions have been handed down to contemporary practitioners. We expect that "extra precautions" were taken because there were no animal studies - all the experimentation was done on humans. It's likely that dosing occurred from the bottom up - the volume of drug as brought up from very little. Having recorded thousands of successful clinical cases makes herbal/traditional/folk medicine widely acceptable there. In combination with unusually low toxicity profiles, folk medicine in China and the east will no doubt continue; particularly the use of tonics (bu-qi-yao; replenish energy) and nutrients (bu-xue-yao; nourish the blood).

    B. Folk Medicine in Different Cultures (the art and the science).

1. Aztec. Tlaloc, the god of water was associated with disease states where water (e.g., phlegm, edema, gout, rheumatism) was retained in the body. Two herbal potions were used to treat the malady. NOTE: Both herbs were termed "hot" by the Aztec culture since they induced sweating.

a. "Yauhtli" (pericon, day flower): contains diuretics (kidneys; water clearance) and diaphoretics (sweating). The concoction was later replaced in Europe by rosemary (St. Mary's herb).

b. "Iztauhyatl" (estafiate, wormwood): contains diuretics and diaphoretics. It was chewed and used also in ritual cleansing (limpias).

2. Zuni. (southwest U.S.; 1000 B.C.) Used the resinous gum of the "pinyon pine" to treat abscesses. Normally, abscess is opened and sprinkled with dried powder. The Pinyon Pine: contains -pinene (75%), -pinene (5%), -cadinene (15-20%). All are antiseptics in modern society and kill Staphylcoccus aureus.

3. India. Practice an entire health care system based upon traditional and herbal medicine called Ayurveda. Loosely translated means "knowledge of life." Ayurveda represents modern integration of herbal and modern medicinal techniques. Scientists in India are well poised to make breakthrough discoveries in medicinal chemistry the next twenty years because they have countless documented cases of successful herbal use and a strong western education and "scientific following."

4. Fiji. 2300 species of plants; 450 recorded and used for medical purposes. Some examples:

a. "Canaga odorata" leaves were used as a remedy for ophthalmia (eye blight). The bark also is used for stomach pains and menstrual cramps. Root of plant used for cancer treatment. Essential oils of the plant contain: pinene, limonene, linalool (germicidal activity), cineole, phellandrene, geraniol, benzyl alcohol (antiseptic), p-cresol, eugenol (used for peptic ulcers, antiseptic), isoeugenol, benzoic acid esters (kills scabies), salicylic acid esters (pro-aspirin). Could be a potentiation of many effects that makes this herbal remedy useful.

b. "Bleekeria vitiensis (dogodogo)" is a small endemic tree reported to have anti-cancer properties. Validated scientifically in the early 1980's. Found 9-methoxyellipticine in the bark and N-methyl-9-hydroxyellipticine in the root. The latter recently made it to clinical trials (mechanism of action: anti-mitotic agent).

a. "Periwinkle:" Vincristine and vinblastine (will be covered later). Locals used plants for years and epidemiologists found low cancer incidence in the population. They arrest cell division so well that they are used in children's leukemia and Hodgkins disease. These compounds altered life expectancy dramatically. Their success story stimulated renewed interest in folk medicine.

6. Australia. Aborigines are a 40,000 year old settlement. All herbal remedies are word of mouth (no physical records). There was no history of hypertension, heart attack, smallpox, cholera, malaria, rabies, tuberculosis, venereal disease, measles and mumps. Europeans brought these maladies to the aboriginal population in 1788 (just like the Spaniards brought to the Pueblos 600 years ago in the US) causing havoc to their health; there was no natural immunity. Herbal medicine evolved (trial and error) combining spiritual beliefs and customs. They also sought a love potion and narcotic. Mostly found perfumes and nicotine-type compounds (which still works to this day!). Sometimes herbal medicine was forced on civilization.

7. China. Several folk and traditional remedies have been defined chemically and pharmaceutically. Some examples of Chinese traditional medicine that continue to be used in the East but also have found their way into Western medical science include:

a. Ginseng (tze-wu-chia). The first published description of its use in medical practice in China was 1596. Two types of medicinal ginseng are recognized; white and red. White is simply the powdered root form and the red version is steamed in caramel. It is as widely used in Korea as China. American ginseng is grown in the Northeast and differs chemically from both these forms. These ginseng formulations are not to be confused with American ginseng tea that is a mixture of many herbs, only one of which is ginseng root. Some more information on ginseng: Japanese Chikusetsu ginseng differs chemically from North American grown ginseng. Chemically speaking, there are about 30 damarane-type triterpenoid [saponin] glycosides designated as ginsenosides (Tet. Lett. 1962, 419). These are monosaccharides (mostly glucose, arabinose and rhamnose). Other compounds present include steroids (-sitosterol), sesquiterpenes (panacene), carbohydrates, Vitamin B and C, choline, peptides and trace elements. American ginseng contains very few ginsenosides with CNS stimulating activity. This American form of ginseng is termed "cooling" and used predominantly for insomnia and indigestion. Red ginseng is a "trophic" (something gained) agent and used for general health and as an antifatigue agent.

There are several scientifically proven positive health effects including:

• Radioprotective: Mice were protected against radiation when given ginseng prior to dose. The results also were dose dependent with more protection afforded from higher concentrations of ginseng (J. Radiation. Res. 1981, 22, 323 and 336).
• Antioxidant: Maltol, salicylic acid and vanillic acid were identified as constituents in ginseng that were capable of destroying "oxidative-type free radicals (e.g., superoxide)." These constituents were found in red but not white ginseng.
• Antitumor and Antiviral Activity: A saponin-containing fraction was potent in suppressing nucleic acid synthesis. The fraction decreased the proliferation of pulmonary adenomas. Certain ginseng extracts were immunostimulants and some showed marked anti-viral activity. The structures have not yet been identified.
• Antifatigue: The antifatigue effects of certain types of ginseng were illustrated by a decrease in -hydroxybutyrate dehydrogenase activity and consequent reduced lactic acid production. Lactic acid concentration builds up in muscle tissue during fatigue and is a common cause of "runners cramp." Virtually all Olympic marathon runners from Japan and China imbibed a ginseng concoction before racing in 1970's and 1980's. Its use may still be in practice but little documentation exists for fear the Olympic committee may someday control ginseng and retroactively disqualify these runners.

c. Gingko Leaves. More recently "gingkolide," the active ingredient in gingko leaves was isolated and found to be a very potent PAF antagonist. It is used as an anti-allergy and as an aid for impotence. Interesting note: The Gingko is the oldest living tree, dating back to the dinosaurs, and has a lifetime of about 1000 years.
 
 

g. Chinese Cucumber. Trichosanthin (Compound Q, GLQ233), a 27 kDa sized single chain ribosome-inactivating protein with 247 amino acid residues, was isolated from the root tuber of a Chinese medicinal herb Trichosanthes kirilowii Maximowicz and was identified as the active component of Tian Hua Fen, a Chinese medicine described as early as the 16th century as a treatment for various kinds of ulcer. Since the discovery of its specific injurious effects on human placental trophoblasts in the 1970's, trichosanthin has been used clinically in China to induce abortion and to treat diseases of trophoblastic origin such as hydatiform mole, invasive mole and choriocarcinoma.  Soon after the laboratory finding in 1989 by McGrath et al. that trichosanthin appeared to inhibit the HIV-1
replication in both acutely infected T-lymphoblastoid cells and in chronically infected macrophages, and selectively killed HIV-infected cells while leaving uninfected cells unharmed, clinical trials of trichosanthin as a potential treatment for HIV were carried out in USA. Trichosanthin attacks the life cycle of the virus at an entirely different point from AZT and related drugs, and in other words, it has a unique mechanism of action complementary to other drugs. Present clinical reports showed that trichosanthin has some curing effects on AIDS patients and suggested it to be a possible treatment that may fill the gap in the treatment of HIV disease.

See:  Ke, YB., Nie, HL. et al., Structure-function relationship of trichosanthin, (1997) Life Sciences, 60(7) 465-472.
 

h. Qinghaosu. New antimalarial (10-100x more powerful than quinine) from traditional medicine. Note the peroxide linkage in Qinghaosu.

i. Other Anticancer Drugs from Chinese Herbal Medicine.

    1. Sesquiterpene Lactones. (alpha-methylene gamma-lactones, alpha, beta-unsaturated cyclopentanones, and alpha-methylenecyclopentenones)

    3. Alkaloids. Vinblastine/Vincristine (bis-indole alkaloids): "Spindle poisons."

Also in this class are podophyllotoxins, colchicine, maytansine, camptothecine (intercalating agent), monocrotaline, indicine, cephalotaxine.

C. Brief Table of Common Herbal Medicines and the Associated Malady
 

The Garlic Story

Garlic. Because garlic holds a prominent place in folk medicine in many cultures (including western), a brief explanation of its heritage and use is presented separate from the one listed above. Garlic has about 5000 years of folk medicine history. It was first used because anything that smelled so strong was thought to contain great power. Aristotle, Hippocrates and Aristophanes all recommended garlic to kill tapeworm and related intestinal parasites. Albert Schweitzer recommended its use to amoebic dysentery, cholera, and typhus. It historical use in several forms of Italian tomato sauces and to repel vampires is unknown.

Researchers found that several components in garlic were indeed active in preventing the aggregation of blood platelets. The most active was "ajoene." The structure is shown below. "Ajo" is the Spanish word for garlic. IUPAC = 4,5,9-trithiadodec-1,6,11-triene-9-oxide. Synthesis and structure see: J. Am. Chem. Soc. 1984, 106, 8295. Review of garlic chemistry and biological activity see: Scientific American 1985, 252, 114.

So, you may ask, what good does it do the garlic plant to lower blood pressure/platelet aggregation? As it turns out, allicin is a powerful antifungal agent and probably was produced by the plant in an effort to ward off invasion of the garlic bulb by fungi.
 

SUMMARY

Before there was modern scientific approaches to drug therapy, there was herbal medicine. Relying largely upon trial and error (often fatal error), cures or least preventative therapeutic approaches were chosen from among the rich plant pharmacy. Modern science has unarguably improved upon this approach leading to miraculous chemical cures. Sometimes, however, the process by which herbal medicines were administered has a great impact upon the medicinal effect. Careful attention must be paid to the holders of traditional medicine knowledge when attempting to bring such important discoveries to the modern laboratory. The process/workup/isolation of a product from a "true" herbal cure may yield a vastly different molecule.

The future holds new challenges to disease states and old challenges yet be answered. The marriage of traditional and modern medicinal chemistry will likely be a fruitful and productive adventure.
 

Literature cited (for the preceding section)
 

Mowry, D.B. "The Scientific Validation of Herbal Medicine," Keats Publishing Inc., New Canaan, CT., 1986.

Steiner, R.P. (Ed.) "Folk Medicine; The Art and the Science," A.C.S., Washington, D.C. 1986

Weiner, M. "Weiner's Herbal," Quantum Books, Mill Valley, CA. 1990.