Mini Reviews in Medicinal Chemistry - Volume 3, Issue 6, 2003

For over thirty years it has been evident that there is altered glycosyltransferase activity in neoplastic tissue when compared to healthy tissue. It has also long been speculated that disruption of the neoplastic expression of sialic acid on cellular glycoconjugates, is a valid target in anti-metastatic therapeutic development. Over the years attempts have been made to synthesize inhibitors of sialyltransferases in a effort to assist in the validation or dissolution of these enzymes as potential therapeutic targets.

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3- b]quinolines (11-13) / 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4- amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15) / 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl- 5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described. These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl [6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2- amino-3-cyano-4,5-diphenylthiophene (20) via Friedländer condensation with selected ketones. These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine. The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine. Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.

The aim of this review is to update current knownledge on the betulinic, ursolic and echinocystic acids and their natural and semisynthetic analogs, focussing on their cytotoxic and anti-HIV activities. Then, the last results of the authors' team on unusual semisynthetic derivatives of these triterpenoids will be presented in order to establish structure / activity relationships.

Man has relied on plants as a source of medicinal agents for centuries. Today, with the specter of antibiotic resistance, emerging infectious diseases, and cancers, phytochemicals continue to provide new structural leads for the chemotherapeutic industry. A number of triterpenoids have shown promise as antineoplastic agents. Members of the cycloartane, lupane, ursane, oleanane, friedelane (especially quinone methides), dammarane, cucurbitacin, and limonoid triterpenoids, have demonstrated anti-proliferative activity on various cancer cell lines. This review covers the recent developments regarding antineoplastic / cytotoxic triterpenoids, excluding saponins, from higher plants.

7-keto-Δ5-steroids have been suggested for the treatment of several diseases. Their significant biological profile resulted in the development of a great number of methods and reagents for the allylic oxidation of Δ5-steroids. These methods and the biological evaluation of the main oxidized Δ5-steroids are summarized.

Extensive evidence supports oxidative stress (OS) via endogenous and exogenous agents as an important factor in induction of autoimmunity. OS arises from the immune system and other endogenous sources. The literature contains support for OS involvement of various drugs and other exogenous substances that produce the condition. Studies reveal prevention or amelioration by antioxidants.

Inhibition of ACAT, the enzyme which catalyses the intracellular formation of cholesteryl esters, is a very attractive target for the treatment of hypercholesterolaemia and atherosclerosis. However, in the past years many ACAT inhibitors gave disappointing results in clinical trials showing very low efficacy. In addition, their development was affected by the adrenotoxicity observed in many compounds. The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, offers a precious information for planning selective inhibitors with reduced secondary effects. Today some potent, bioavailable and non adrenotoxic ACAT inhibitors are under clinical evaluation. Amongst others, a very promising compound is Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent. Finally, ACAT inhibitors have recently been proposed for the treatment of Alzheimer's disease.

Since the discovery of E-64 in 1978 as potent cysteine protease inhibitor a variety of inhibitors containing small rings as electrophilic building blocks responsible for enzyme inhibition have been developed. In this review we summarize new aspects concerning epoxysuccinyl peptides derived from E-64 and discuss inhibition potency, selectivity and mechanisms of peptidic and peptidomimetic inhibitors containing epoxide, aziridine, thiirane, cyclopropane, ß-lactam and ß-lactone rings as electrophilic fragments.

Diseases caused by parasitic protozoa present a health problem of immense magnitude, and there is an urgent need for safe and effective new therapies. DNA topoisomerases are clinically relevant targets for anticancer and anti-bacterial agents. Inhibitor studies on parasite topoisomerases have revealed that these enzymes have great promise as molecular targets for anti-parasitics, and have helped to dissect the basic biology of DNA topoisomerases in these organisms. This review provides a brief introduction to DNA topoisomerases and anti-topoisomerase drugs, and an overview of studies on protozoal DNA topoisomerases and their inhibitors.

A hydroxamic acid moiety has been demonstrated as the key structural element in many highly potent and selective inhibitors against a variety of metalloprotease enzymes, such as MMPs, TACE, HDAC, PDF, etc. Over the last several years, there has been a rapid growth of literature and patent applications dealing with the development of the hydroxamic acid-based inhibitors. This review highlights the most recent examples to show their potential therapeutic applications.

Hypertension remains one of the most unmet medical needs of this century. While many drugs are available for treating hypertension, efforts are still insufficient to find potent therapeutic agents since cause for hypertension in all patients is not the same. Angiotensin-converting enzyme inhibitors (ACEIs) have emerged as an important class of drugs in the treatment of hypertension, congestive heart failure (CHF), protenuric renal disease, myocardial infarction and stroke. This class of drugs blocks the conversion of angiotensin I to angiotensin II and prevents bradykinin breakdown. However, the lack of specificity of ACEIs leads to the frequent side effects like cough and angio-oedema. Recently developed, specific non-peptide and orally active angiotensin receptor blockers (ARBs) have become the prime therapeutics as they alone or coadministration with ACE inhibitors can control the renin angiotensin disorders. This review explores recent developments in the design, synthesis, and structural modifications of ACE inhibitors as well as angiotensin receptor blockers.