Aplicación de la metodología HCM 2010 en la propuesta de la

n NOMENCLATURE. A wide variety of tricyclic heterocycles, some of which are of medicinal significance, might be presented. Three representative nuclei are shown in Figure 15-57: phenothiazine, dibenzazepine, and acridine. The nomenclature and numbering of these heterocycles are as shown. Note that the numbering system for each of these compounds is unique.

n PHYSICAL-CHEMICAL PROPERTIES. The phenothiazine nucleus contains a nitro-gen that should be considered nearly neutral. Two aromatic rings attached to a ni-trogen, each withdrawing electrons, reduce the basic property significantly. In most cases, this nitrogen will not form a salt with acid. The same reasoning holds for the nitrogen in 5H-dibenz[b,f]azepine. Acridine, although a weak base, can form salts with a strong acid.

An interesting physical property of the phenothiazine nucleus is that the mole-cule is not flat (Fig. 15-58). The shape of this molemole-cule is thought to affect its bio-logic activity, and the amount of bend from planarity therefore may be important.

A characteristic of the acridine nucleus is the fact that the molecule possesses color. The nature of the color depends upon the substituents added to the three rings. The fact that a molecule possesses color indicates a highly conjugated mole-cule with alternating single and double bonds. With three conjugated rings, a yel-low coloration is seen.

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S N H

FIGURE 15-58. Conformational structure of phenothiazine.

n METABOLISM. The characteristic metabolism found in all three of the tricyclic compounds is aromatic hydroxylation. Since the medicinally useful agents have sub-stitution on these nuclei, the subsub-stitution will influence the site of hydroxylation.

An additional metabolism common to the phenothiazine nucleus is oxidation of the sulfur to the sulfoxide or sulfone. This reaction can be expected for any thioether and was discussed previously (see Fig. 8-6).

C a s e S t u d y 1 5 . 1

Having taken an academic position at a prestigious pharmacy school after com-pleting your postdoctoral education, you have quickly become one of the most highly respected teachers in the program. Students and colleagues alike appre-ciate your commitment to interdisciplinary collaboration and content integra-tion, and the fact that you regularly reinforce the importance of medicinal chemistry in the rationale design and therapeutic use of drugs.

You have just started a series of lessons on diuretics and designed a structure-based therapeutic challenge for the class that involves the popular diuretic

NH

FIGURE 15-57. Structure of representative tricyclic heterocycles and examples of drugs containing these heterocycles.

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C H A P T E R 1 5 ⁿH E T E R O C Y C L E S 131

C a s e S t u d y 1 5 . 1

furosemide (Lasix). Specifically, you asked your students to identify two hetero-cyclic functional groups out of five choices that would be bioisosteric with furosemide’s oxygen-containing ring. To be bioisosteric, the replacement rings must have essentially the same chemical properties as the original ring so that the original biological activity could reasonably be assumed to be maintained.

Cl

COO SO2

HN O

H2N

Furosemide (Lasix)

Ring of interest

Ring replacement candidates:

N H

N

O H

N N

HN

1 2

3 4 5

Having completed the in-class exercise, your students are now clamoring for you to reveal the correct choices. Use the space below to write your answer key.

C a s e S t u d y 1 5 . 2

You are a first year pharmacy student and are given the following case-based exami-nation question in the course in organic functional groups. The professor wants to test your ability to apply knowledge gained from the chapter on heterocycles.

PM, a 65-year-old Caucasian female, recently suffered an episode of uric acid renal stones. PM has a history of asymptomatic hyperuricemia (plasma uric acid ~9.5mg/dL). She developed severe diarrhea while on a vacation cruise, which she said was brought on by something she ate. She knew enough to hy-drate and did so with copious quantities of cranberry juice, which acidifies the urine. However, PM developed nausea, vomiting, and intolerable flank pain, which made her seek out the ship’s doctor. Given PM’s history of hyperuricemia the doctor made a diagnosis of uric acid kidney stones and treated PM with sodium bicarbonate (4 g stat, then 2 g every 4 hours not to exceed 16 g a day) and told her to immediately stop drinking cranberry juice and switch to 2 to 3 L of water a day.

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C a s e S t u d y 1 5 . 2

Given that uric acid, the end product of purine metabolism, is a weak acid (pK_a⫽ 5.5) formed by the action of xanthine oxidase on xanthine, and that PM’s urinary pH is 5.0 answer the following questions:

1. Why did the doctor tell PM to immediately switch from cranberry juice to water?

2. What is the role of sodium bicarbonate in treating uric acid kidney stones?

3. Given that the most acidic functional group of uric acid and phenol are aro-matic alcohols (phenolic hydroxy groups), can you explain the almost 1,000,000-fold difference in their pK_as (phenol pK_a⫽ 11, uric acid pKa⫽ 5.5)?

Metabolic degradation of the purine nucleotide adenosine monophosphate to uric acid.

HN

By far the most important chemicals in all living cells are the nucleic acids deoxyri-bonucleic acid (DNA) and rideoxyri-bonucleic acid (RNA). These polymeric molecules are the sources of all information needed for the construction of a living organ-ism and the production of the proteins that run the organorgan-ism, respectively. DNA found in the nucleus of eukaryotic cells is a double-stranded polymer that makes up the genes of an organism. DNA uncoils into a “sense” strand of nucleic acid and an “antisense” strand. The “antisense” strand is transcribed into messenger RNA (mRNA), which has the same sequence as the “sense” strand of DNA. The mRNA leaves the nucleus and in the ribosome serves as the template defining the sequence for protein synthesis. Thus, DNA and its messenger RNA prescribe the construc-tion of all of the proteins of the body that carry out the day-to-day funcconstruc-tion of the living organism.

n NOMENCLATURE. The two nucleic acids, DNA and RNA, are made up of four heterocyclic bases: guanine, adenine, and cytosine (common to both DNA and RNA) and uracil or thymine, present in RNA and DNA, respectively (Fig. 16-1).

As discussed in Chapter 15, guanine and adenine are purines, while cytosine, uracil, and thymine are pyrimidines. Two pentoses are present in the nucleic acids, and these pentoses are ribose or deoxyribose in RNA or DNA, respectively. When the pentoses are attached to the N-9 position of the purines or the N-1 position of the pyrimidines, the resulting product is named a nucleoside. The suffix “-side” in-dicates the presence of a sugar. Attachment of the sugar to the bases occurs at the 1⬘ position of the sugar. The linkage between the sugar and the heterocyclic base is through an acetal functional group. Finally, a phosphoric acid is added to the 5⬘ position of the pentose to give the nucleotide. The phosphate attachment to the sugar is considered an ester group. Nucleic acids result from the polymerization of nucleotides through ester formation of the 5⬘-phosphate to the 3⬘ alcohol of the pentose (Fig. 16-2). The continuous chain of pentose-3⬘,5⬘-diester is present as the backbone to this polymer.

An oligonucleotide is a short-chain polymer of nucleotides with the same three components: base, sugar, and phosphate ester. The significance of oligonucleotides is that they represent a new approach to drug therapy, and such agents are referred to as “antisense drugs.” Such drugs are designed to block protein synthesis in dis-eases associated with an abnormal protein and overexpression of a normal protein.

The antisense drug is designed to interact with mRNA through Watson-Crick base pairing, leading ultimately to the blockage or termination of the action of mRNA.

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