Chapter 2
Drugs Based on Carbohydrates Past and Future M. Petitou
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Department of Carbohydrate Chemistry, Sanofi Recherche, 9, rue du Président Salvador Allende, F-94256 Gentilly, France
Several drugs currently available contain a carbohydrate structure. They are reviewed in the first section of the chapter. The second section is devoted to current research aimed at the improvement of existing drugs and the discovery of new leads. Minor improvements of existing drugs may consist of a slight modification of their biological profile, but major improvements, based upon the elucidation of the mechanism of action, may result in completely new drugs. Although biological screening of carbohydrate derivatives may provide new active principles, most of them are expected to come from research in glycobiology, a new, rapidly expanding, domain of biology.
Carbohydrate containing drugs have been used for a very long time: they can be traced back to 1600 BC to ancient Egyptian manuscripts, where a medicinal prescription of the squill bulb shows the use of cardiotonic glycosides. Prescription of the squill bulb was again reported two centuries later, in the Corpus Hippocraticum, to produce diuresis. Much later (1785) William Withering reported on the use of the foxglove, but it was only in 1869 that the different components and particularly digoxin, were purified by Nativelle. Digoxin and several other cardiac glycosides (17 International Nonproprietary Names -INN- could be counted in 1991 (1)) are still used nowadays and research in the field is going on. Numerous other drugs, although with a shorter and less exciting history, contain a carbohydrate or a carbohydrate derivative, and altogether one can list more than 150 different INNs of carbohydrate-based active principles (i). The origin of all these different drugs is diverse: some, like the cardiac glycosides, have been extracted and identified in old medicines. Others derive from the known biological function of their parent carbohydrate. Finally, some others have been invented by screening carbohydrate derivatives as for any other chemicals. For the sake of completeness one
0097-6156/94/0560-0019$08.00/0 © 1994 American Chemical Society
In Synthetic Oligosaccharides; Ková, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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should also mention those drugs (related to the latter category) that contain a carbohydrate as a carrier of pharmacophores: for example "mannitol hexanitrate" (vasodilator containing mannitol), "isosorbide dinitrate" (vasodilator containing l,4:3,6-dianhydro-D-glucitol), "Calcium glucoheptonate" (mineral agent containing D-gluco-heptonic acid), "Ferrous Gluconate" (antianemic containing D-gluconic acid), in all of them the role of the carbohydrate-derived entity is probably not of prime importance. Nowadays pharmaceutical research in the field of carbohydrates follows the same lines: improve old drugs; discover new leads based on recent breakthroughs in the biology of carbohydrates, or discovered by chance, by screening the hypothetical properties of any available chemical entity. The first section of this article is devoted to existing carbohydrate containing drugs. The second explores the current areas of research. Carbohydrate-Based Drugs of Today. Cardiac Glycosides. We have already mentioned this class of compounds (see above). Each cardiac glycoside results (Figure 1) from the combination of an aglycon (genin) linked to a glycon (a carbohydrate, mono- to tetrasaccharide). The mechanism of action, which is still being debated (2) involves inhibition of a membrane N a , K ATPase. Pharmacological activity resides in the aglycon and the carbohydrate +
ÇH
+
3
Figure 1. Digitoxin component modifies the solubility, potency and pharmacokinetics (3). The most important therapeutic use of digitalis is to treat heart failure. Research is still going on to improve the monitoring of these very efficient drugs. Aminoglycoside Antibiotics. With about thirty members (1), the aminoglycoside antibiotics family is the largest family of carbohydrate containing drugs. The first member, streptomycin, was discovered in 1944 and its clinical efficiency proved in 1949. The aminoglycosides (Figure 2) consist of generally two (sometimes three as in neomycin) amino-deoxy monosaccharides joined in glycosidic linkages to an aminocyclitol (streptidine or 2-deoxy-streptamine) usually placed in a central position (although it may be terminal as in streptomycin) (4). Aminoglycosides interfere with protein synthesis mainly through binding to 30S ribosomal subunits in susceptible organisms. They are used primarily to treat infections by aerobic gram negative
In Synthetic Oligosaccharides; Ková, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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Drugs Based on Carbohydrates
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bacteria. The most widely used are gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin and neomycin. Most of them are produced by fermentation
NH
2
OH
Neomycin Β Figure 2. Aminoglycoside antibiotics. techniques, and sometimes semisynthesis is used to improve activity or bioavailability since they are poorly absorbed after oral administration. Thus amikacin derives from kanamycin and netilmicin derives from sisomicin. The same pattern of toxicity is shared by all members of the group: ototoxicity mainly, and nephrotoxicity. This severely restricts the use of these essential antibiotics. Research is still going on, at a low rate, in this domain and several products are under clinical trial; isepamicin is among the most promising candidates. Other Carbohydrate-Containing Antibiotics. Macrolide Antibiotics. These compounds (erythromycin etc..) contain one large lactone ring to which one or several deoxy-sugars are attached, the activity of which is not very well known. Of course the lipophilic or hydrophilic character of the molecule is modulated by the presence of the carbohydrate moiety. Macrolide antibiotics inhibit protein synthesis by binding to the 50s ribosomal subunits of sensitive microorganisms.
In Synthetic Oligosaccharides; Ková, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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Clindamycin (Figure 3). This drug contains a substituted methylthio octoside, which can be esterified to produce a prodrug (clindamycin palmitate).
Figure 3. Clindamycin Antiviral Agents. Most of the currently used antivirals are derivatives or analogs of purine or pyrimidine nucleosides. All these agents interfere with DNA synthesis or transcription, and some can be used as antimitotics and anticancer drugs. Those which have specific antiviral activity need to be phosphorylated by a viral kinase or act at the level of reverse transcriptase (in the case of retro-viruses). Ribavirin is a pure nucleoside analog that inhibits the replication in vivo of a wide range of RNA and DNA viruses. Zidovudine (AZT) 3'azido-3-deoxythymidine (HIV-1) is phosphorylated in vivo to the corresponding deoxynucleoside triphosphate which inhibits the viral reverse transcriptase. Vidarabine (arabinosyl adenine) is active against the herpes virus (see Figure 4). Idoxuridine and Trifluridine are fluorinated pyrimidine which also inhibit viral DNA synthesis. ,
Figure 4. Zidovudine (left) and Vidarabine. Anticancer Agents. Numerous anticancer agents, either isolated from natural sources or chemically synthesized, are glycosylated: Pyrimidine nucleoside analogs inhibit the synthesis of pyrimidine nucleotides or they mimic the metabolites to such an extent that they interfere with vital cellular functions such as the synthesis of nucleic acids. Cytarabine (AraC) is an analog of 2deoxycytidine. It is the most important antimetabolite used in the therapy of acute myelocytic leukemia.
In Synthetic Oligosaccharides; Ková, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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Downloaded by UNIV OF ARIZONA on January 14, 2013 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0560.ch002
Purine nucleoside analogs are also used: pentostatine (2'-deoxycoformycin) is an inhibitor of adenosine deaminase (inhibits purine synthesis) which has a certain clinical efficacy against some leukemias and lymphomas. Anthracycline antibiotics are an important class of anticancer drugs. Daunorubicin, doxorubicin and idarubicin are commonly used either alone or in combination, to treat acute leukemias and various types of solid tumors. They can damage DNA (via super-oxide radicals) and prevent its repair, intercalate with DNA, and/or inhibit RNA synthesis. They contain the monosaccharide L-daunosamine with other analogs containing di- and trisaccharides.
NH
2
Figure 5. Daunorubicin, R = H; Doxorubicin, R = OH In contrast, in the recently discovered calicheamicins group of antitumor agents, the aglycon is responsible for the cutting of the DNA molecule, whereas the specificity is directed by the complex carbohydrate-aromatic fragment which interact with the minor groove of the DNA (5). Another cytotoxic antibiotic, Plicamycin, contains one disaccharide and one trisaccharide (
