Antineoplastic Drugs

Organic Syntheses

Daniel Lednicer

• Publisher: Wiley
• Year: 2015
• Print ISBN:
  9781118892541
• Edition: 1
• eBook ISBN:
  9781118892565
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

The past decade has seen a significant increase of research aimed at discovering new drugs for treating cancer, and the increasing number of new antineoplastic drugs approved by regulatory agencies reflects this. Until now, details on the synthesis of these newer agents have been scattered in various journals and in US and European patents. This timely volume deals with the organic chemistry involved in the synthesis of the agents found within antineoplastic drugs, including descriptions of the synthetic schemes for the preparation of over 200 compounds that have been granted non-proprietary names. Compounds are collected in chapters based on the mechanism of action rather than on their chemical structures. Each individual chapter is preceded by a brief description of that mechanism and includes detailed flow charts of the preparation of those compounds accompanied by discussions of the organic chemistry involved in each step. The first half of this volume is dedicated to the syntheses of established chemotherapy drugs. Kinase inhibitors occupy the following chapters with the largest single chapter dealing with the fifty compounds that inhibit tyrosine kinase. This class stands out since over twenty compounds in this group have been approved for treating patients; a rare track record compared to any other class of therapeutic agents. Antineoplastic Drugs: Organic Syntheses is written to appeal to organic and medicinal chemists in industry and academia. It is beneficial to those composing grant proposals for NCI and related organizations. The book is accessible to advanced undergraduates as well as graduates and researchers as well as those with a thorough grasp of organic chemistry.

1
Alkylating Agents

An impressive number of cytotoxic compounds whose antineoplastic activity is due to their reactions with DNA have been studied in the clinic. Many of these comprise drugs that currently form part of the combinations used to treat neoplastic disease. This account however includes only a limited number of alkylating agents since this area has been well covered elsewhere.

1.1 bis-Chloroethyl Amines

As noted in the Introduction, antineoplastic agents that include in their structure highly reactive chemical moieties comprise the earliest class of drugs for treating malignant tumors. This applies particularly to those cancers that afflict the system for producing and maintaining blood-forming tissues such as leukemia and lymphoma. The first of these agents, mustine (1.1), also known as mechlorethamine, was, as noted in the Introduction, actually developed empirically. An understanding of the mechanism by which alkylating agents kill cancer cells awaited the discovery of the structure of DNA in the 1950s as well as elaboration of the chemistry for studying that substance. The relatively large group of alkylating anticancer drugs was actually synthesized before their mode of action was fully understood. Many of those anticancer agents were designed as analogues of prior compounds that sported the chemically reactive chloroethyl group or some other highly reactive function.

The alkylating agents as a class attack many tissues in the body that contains basic nitrogen. Those agents target all cells that are susceptible to alkylation, be they cancerous cells or unrelated normal cells. The latter circumstance leads to many classical side effects manifested by alkylating antineoplastic drugs, such as loss of hair, dry mouth, and dry eyes, experienced by patients exposed to this class of antineoplastic agents. The effects on neoplastic cells are however more relevant to this discussion. Reaction with DNA is not a random process; it has been shown that alkylating agents react preferentially with the more electron-rich, more basic nitrogen atoms in DNA. The stacked bases between the two strands of that macromolecule in the helical arrangement constitute a particularly favorable configuration for attack on each of the two separate strands of DNA. Drugs that incorporate two alkylating moieties form a covalent bridge between the two strands of DNA. This effect is demonstrated by the significantly lower concentration of bifunctional agents required to kill cancer cells in vitro than that of molecules that include only a single reactive group. That cross-link inactivates alkylated DNA since almost all functions of DNA, such as replication, require access to a single strand. RNA, the counterpart directly involved in synthesizing new protein, can only read a single DNA strand. The affected cell then simply ceases to function and dies. Although very large number of alkylating drugs has been studied since the early 1940s, the present account is restricted to five subsets that illustrate research in this field.

The chloroethyl group found in this subset of alkylating drugs does not react with DNA as administered. Instead, the basic nitrogen in mustine (1.1) displaces the side chain chlorine to form an aziridinium salt (1.2). The reaction of this activated species with nitrogen in DNA leads to ring-opened DNA adduct. The repetition of that sequence with the second chloroethyl function followed by the reaction of the new aziridinium function with alkylated DNA leads to cross-linked DNA.

Scheme 1.1 Aziridinium salt formation.

The first recorded preparation of this rather venerable antineoplastic agent involves the reaction of methyl-bis(hydroxylethane) (2.1) with thionyl chloride. The starting diol is speculatively available from the reaction of methylamine and ethylene oxide. The resulting product, mustine (2.2), needs to be handled as a positively charged salt to prevent ex vivo aziridinium formation [1].

Scheme 1.2 Synthesis of mustine.

Cyclophosphamide is one of the best known and widely used antineoplastic agents. The drug comprises “C” in a large number of multidrug cocktails for treating cancer. One of the several schemes for preparing this compound starts with the condensation of aminoalcohol (3.1) with phosphorus oxychloride to afford the oxazaphosphorine derivative (3.2) through stepwise displacement of halogens in phosphorus oxychloride by the base and alkoxide group in (3.1). The still reactive chlorine in that product is then displaced with 2-chloroethylamine (3.3). The same reagent is then used to add a second chloroethyl function. This brief sequence affords cyclophosphamide (3.5) [2].

Scheme 1.3 Cyclophosphamide.

This drug is actually not the active alkylating species. Instead, enzymes open the ring by first hydroxylating the carbon bearing oxygen. The resulting hemiacetal then hydrolyzes to afford the phosphoramide mustard species (3.6). This has been approved for clinical use by many regulatory bodies. It is available as a generic drug since the patent covering this entity expired many years ago.

Scheme 1.4 Estramustine.

It is widely known that a large proportion of human female breast and possibly...

Table of contents

• Cover
• Title page
• Table of Contents
• Preface
• Introduction
• 1 Alkylating Agents
• 2 Antimetabolites
• 3 Hormone Blocking Anticancer Drugs
• 4 Topoisomerase Inhibitors
• 5 Mitotic Inhibitors
• 6 Matrix Metalloproteinase Inhibitors
• 7 Histone Deacetylase Inhibitors
• 8 Enzyme Inhibitor, Part I, Tyrosine Kinases
• 9 Enzyme Inhibitors: Part II Additional Targets
• 10 Miscellaneous Antineoplastic Agents
• Appendix A
• Index of Heterocycle Syntheses
• Subject Index
• End User License Agreement