Ochiai E. Chemicals for Life and Living

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7 Stories of Drug Developments

It takes about 2 h for the half of chlorides of cis-platin being displaced by water

molecules at the body temperature, 37°C. This might be considered as an activation

process. The Pt(II) complex now binds readily with DNA at a place called “N-7

nitrogen atom” of a guanine residue (G). [DNA is a chain of four different units

designated as A, C, G, and T; see Chap. 4.] When Pt(II) binds G (and sometimes

also with A), it disrupts the normal structure of DNA and hence its replication. It has

recently been shown that cis-platin upon binding brings about a sharp kink in the

double helix DNA, to which a protein called “high-mobility-group” (HMG) binds.

In particular, a phenyl alanine residue on HMG inserts itself into the bent portion of

DNA. How this will play out in the disruption of DNA duplication is not known.

So, as long as cis-platin enters exclusively into the tumor cells, it would work

wonders. Because tumor cells are in rapid replication mode, they have more chance

than ordinary cells to be affected by the platinum compound. And this is the reason

for the effectiveness of cis-platin. However, it is likely that cis-platin enters other

kinds of cells, too. This would lead to toxic side effects. Indeed, there are some

severe side effects including diarrhea and nausea.

The recent efforts have been aimed at synthesizing cis-platin analogues that

exhibit lower toxicity and have higher antitumor activity than cis-platin itself.

Hence, various analogues of cis-platin such as cis-diammine(cyclobutane-1,

1-di-carboxylato)-platinum(II) or carbo-platin, 1,2-bis(aminomethyl)cyclobutane-

platinum(II) lactate or loba-platin, and their derivatives have been studied in tumors

that have exhibited cis-platin resistance. These are called “second generation platinum

compounds.” For example, carbo-platin that entered a clinical trial in the early 1980s

has been shown to be effective against ovarian cancer and undergoes a reaction

similar to that of cis-platin.

7.6 Curry, Another Anticancer Agent?

The bright yellow active ingredient of curry is a chemical called “curcumin.” It has

been discovered that curcumin slows the growth of new cancer. A Korean scientist,

Ho Jeong Kwon, at Sejong University has shown that curcumin inhibits irreversibly

an enzyme, aminopeptidase N (APN). APN breaks down proteins at the cell surface

and helps cancer cells to invade the intercellular space. This is believed to lead to

angiogenesis, that is, blood vessel growth. Hence, curcumin arrests angiogenesis,

and hence cancer cells become unable to get blood to grow. It has been suggested

that it might not have any signiﬁcant side effects since curcumin is a regular ingredient

of natural diet. How does curcumin do this? What is the mechanism of inhibition?

This is yet to be studied.

Fig. 7.8 Cis-platin (the broken

lines show the framework, not

the bonds)

1037.7 PILLS: Controls of Reproductive Systems by Hormones and Their Analogues

7.7 PILLS: Controls of Reproductive Systems by Hormones

and Their Analogues

The so-called “pill” freed women from worries about becoming pregnant, and hence

revolutionized the man–woman relationship and then the overall human society at least

in the Western countries. Human sexuality and pregnancy are governed by sex hor-

mones. The representatives of sex hormones are estrogen and progesterone (these two

are female sex hormones), and testosterone (male sex hormone). Estrogen is a collec-

tive name for estradiol and similar compounds including estrone and estriol. Estradiol

is the most abundant and most effective estrogen. All these compounds belong to a

group of compounds called “steroids” that also include cholesterol as well.

Is not everybody worried about cholesterol? And cholesterol is a steroid. Well

then, are not steroids bad? What are steroids, anyway? Chemically, they belong to a

group of compounds called lipid. Lipid is a fancy (collective) term for oil-soluble

compounds and includes fats, phospholipids, and steroids. Fats are chemically long

chain fatty acids and almost like wax. Phospholipids are combination of fatty acids

and glycerine with some special groups on top and make up the membrane of cells

(Fig. 1.5). By the way, cholesterol also makes up an essential part of cell membranes

along with phospholipids. Cholesterol is indeed a necessity. Only excess presence

of cholesterol is a health hazard.

Steroids are classiﬁed as lipids, only because they are soluble in oil, but they are

quite distinct from the other lipids. Steroids all have a special skeletal chemical struc-

ture, as shown in Fig. 7.9, and all are chemically very similar. How closely they are

similar can also be seen in their 3D structures. The 3D structures of estradiol and

testosterone are shown in Fig. 7.10. They appear almost indistinguishable. A major

chemical difference is that estradiol has one hexagonal group (the left-hand most) that

is like benzene, i.e., three double bonds instead of one as in progesterone and testos-

terone, and that ring lacks a methyl group (CH

). The other female sex hormone,

progesterone, is in these respects similar to testosterone. The difference between them

occurs at the other end: CH

CO-group in progesterone vs. HO-group in testosterone.

The whole point here is that the structural differences are rather small and subtle

among the sex steroid hormones, and yet that they elicit very different physiological

responses. [Sexual hormonal systems involve more than steroid hormones, such as

follicle-stimulating hormone (FSH), luteinizing hormone (LH), and others].

Estrogens are normally secreted by the ovaries and induce syntheses of a series

of proteins that manifest as feminine characteristic features in such organs and tissues

as the female sex organ, the breast, and the fatty tissues. Progesterone instead is

mostly involved in pregnancy. Menstruation is caused by the sudden reduction in

both estrogen and progesterone at the end of the monthly ovarian cycle. Progesterone

is secreted by the corpus luteum in nonpregnant women, but is formed in extreme

quantities by placenta when a woman is pregnant.

Testosterone is mainly produced and secreted by the interstitial cells of Leydig in

the seminiferous tubules of testes. It affects the development of the male sexual

organ and has effects on body hair, muscle, bone calcium, and others.

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7 Stories of Drug Developments

Cholesterol

Progesterone

Estradiol

DiethylstilbestrolRU-486

Testosterone

Cortisol

C=O

Fig. 7.9 Steroids

Fig. 7.10 Estradiol (upper)

versus testosterone

1057.7 PILLS: Controls of Reproductive Systems by Hormones and Their Analogues

A steroid, being a lipid, has a high afﬁnity to cell membranes, and hence it can

enter a target cell readily, requiring no special mechanism. A steroid hormone binds

with a receptor protein in the cell. The receptor–hormone complex is then trans-

ferred into the cell nucleus. The receptor protein binds to a speciﬁc place of DNA in

the cell nucleus, with or without a steroid bound. However, when the receptor protein

binds a steroid, it changes its structure (conformation) and becomes able to bind yet

another factor (protein) called a “coactivator.” The binding of a coactivator to the

DNA–receptor–hormone complex acts as a signal to start transcribing a portion of

the DNA into a messenger RNA (m-RNA). That is, the receptor–hormone (plus

coactivator) complex acts as a “transcription factor.” As with other common tran-

scription factors, many of the steroid hormone receptors contain a portion of the

so-called zinc-ﬁnger as mentioned earlier (Sect. 6.4). The cell machinery then syn-

thesizes a new protein from the copy of the m-RNA, and hence, the manifestation of

a physiological effect. An example of such complex, hormone–receptor–DNA, is

shown in Fig. 7.11. The process of synthesizing proteins (DNA → m-RNA → protein)

is discussed in Chap. 4.

7.7.1 The Pills

The idea of the pill was suggested by Margaret Sanger, a lifelong champion of

women’s rights and birth control. In 1950, she met a reproductive scientist Gregory

Pincus and raised money to get Pincus started on a research on contraceptives. It had

been known since 1930s that administration of excess hormones, estrogen and pro-

gesterone, prevents ovulation in rabbits. Pincus used progestins as contraceptive,

which he tested on poor women in Puerto Rico. By the end of 1960s, a contraceptive

pill became widely available in the United States and was welcomed by women.

The earlier pills had high contents of hormones, both estrogens and progestins, and

were recognized later to be quite an overdose. Today, the pills contain a much less

quantity of estrogens and progestins, often progestins only.

Fig. 7.11 Hormone receptor; (a) zinc-ﬁnger portion binding to a DNA and (b) hormone-binding

segment with estradiol bound [from J. Berg, L. J. Tymoczko, and L. Stryer, “Biochemistry, 5th ed”

(W. H. Freeman, 2002)]

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7 Stories of Drug Developments

The mechanism of contraceptive action is believed to be that the presence of an

extraneous quantity of these hormones, particularly progestin, mimics the hormone

condition of pregnancy. Hence, the body mistakes itself as being pregnant and

suppresses ovulation. Recall that progesterone is secreted in a large quantity by

placenta when a woman is pregnant.

What kind of progestin would work well? The indigenous hormone, progester-

one, will work, but will the administration of progesterone itself be a good idea?

Besides, production of progesterone may not be easy. These thoughts led chemists

to an idea of using chemically synthesized analogues of progesterone and estrogen,

particularly those that can be administered orally. The term progestins used above

means any compound that has the basic progesterone skeletal structure. Carl

Djerassi, a Stanford chemistry professor, and others managed to synthesize several

such compounds. Some of such compounds are shown in Fig. 7.12. You can see

their overall similarity to either of the natural hormones, progesterone and estrogen.

Although the chemistry of synthesizing these compounds is quite difﬁcult (and

cannot be discussed here), their effectiveness can be gleaned from a look at their

overall structures. In reality, the physiological effectiveness of each compound is

determined by many factors in addition to the global structures. Such factors include

how a compound is delivered to the target and how it is metabolized.

7.7.2 RU-486

RU-486 is a product of a French company, Roussel-Uclaf. Chemically, it should be

named as11-(4-dimethylaminophenyl)-17-hydroxy-(proy1ynyl)-estra-4,9-diene-3-

one. When used in conjunction with a synthetic prostaglandin, RU-486 has been

C=O

CCH

Progestins

Norethindrone

19-Norprogesterone

Progesterone

Estradiol

Mestranol

(a syntetic estrogen)

C CH

Fig. 7.12 The pills

1077.7 PILLS: Controls of Reproductive Systems by Hormones and Their Analogues

demonstrated to be effective in terminating pregnancy up until 9 weeks after the

previous menstrual period. RU-486 has been shown to bind three times more

strongly to the progesterone receptor than the endogenous progesterone itself.

Let us look at the chemical structure, as compared to progesterone (Fig. 7.9). The

antagonist (RU-486) possesses a bulky dimethylaminophenyl group, which may

prevent the binding of a coactivator that is required for activation of gene transcrip-

tion. This antiprogesterone activity blocks development of the endometrium, which

is necessary for implantation of the blastocyst, thus stopping the further progress of

pregnancy. Six-hundred milligrams of RU-486 followed by administration of one or

two synthetic prostaglandins 36–48 h later has been reported to be 96% effective in

terminating pregnancy. RU-486 was approved by US FDA in September 2000.

Part III

For the Fun of Life

Chemicals are also involved in entertaining us. Our lives would be desolate without

their efforts to entertain us. A few areas where we are entertained by chemicals are

talked about in this part, including ﬁreworks, light show by ﬁreﬂy and others,

ceramic artworks, diamonds, and perfumes. One of the emphases here is the basis

of the visual arts, i.e., the phenomenon of “color.”

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E. Ochiai, Chemicals for Life and Living,

8.1 Firework: A Chinese Invention

Boom! Bang! Millions of stars of red, yellow, and green. Oh! Wow! On July 4th the

American sky is covered with hundreds of thousands of ﬁreworks all over the nation.

It is estimated that more than 100 million dollars are spent on this spectacular

display of chemicals on this day. This is perhaps one of the most ancient uses (con-

scious uses) of chemicals for the purpose of enjoyment. The essential ingredient is

gunpowder that detonates and helps display millions of colored particles. Gunpowder

is that black stuff, and used for what else but gun; the same stuff.

Fireworks were actually invented by Chinese alchemists who sought the elixir of

immortality, as recorded in a book (Methods of the Various Schools of Magical Elixir

Preparations) published around 650 ad. What an irony! Chinese people love to use

explosives for celebrations. As early as 200 bc as recorded in chronicles, they threw

pieces of bamboo into ﬁres; the bamboo would explode with a bang. By the way, the

Chinese word for ﬁrecracker is still “explosive bamboo.” So when the gunpowder

became available, it is only natural that they utilized it for the purpose of ﬁreworks.

Fireworks: A Carnivals of Chemicals