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IntroductionSingle coronary artery is a rare anomaly, which is usually associated with other cardiac congenital abnormalities.Case ReportA 56-year-old female presented with unstable angina. The patient reported complaints of typical chest pain on exertion few months prior to presentation, which progressed to become at rest. The pain was associated palpitations and dizziness. Past medical history was significant for hypertension and hyperlipidemia. Vital signs were stable. Physical examination was non-remarkable. Electrocardiogram showed normal sinus rhythm, with intermittent episodes of sinus bradycardia, and non-specific T-wave changes. Trans-thoracic echocardiogram showed normal left ventricular function and no segmental wall-motion abnormalities. Selective coronary angiography showed a normal left main coronary artery arising from left coronary cusp. The left main branched to a normal left anterior descending artery and to the left circumflex artery; a large vessel which supplied also the territory of the right coronary artery (RCA) through its terminal extension. Aortography showed absence of RCA with no other vessels arising from the right or non-coronary cusps. The patient was managed conservatively and discharged home with resolution of symptoms.ConclusionsWe report a rare case of isolated single coronary artery with absent RCA. The patient presented with unstable angina, and was managed conservatively. Cardiologists should be aware of this rare condition, which carries a potential risk of sudden cardiac death.

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A number of substrate analogues of N8-acetylspermidine (N8-AcSpd) (16) and chemical modifying agents containing metal coordinating ligands were assayed as inhibitors of the cytoplasmic enzyme N8-AcSpd deacetylase from rat liver. The enzyme is inhibited by metal chelators, several omega-amino-substituted carboxylic acids, and some thiol reagents. Inhibition by diisopropyl fluorophosphate was observed only at high concentrations. These results suggest that the catalytic mechanism of the enzyme requires a transition state metal and free sulfhydryl groups for activity. The most potent inhibitor synthesized 6-[(3-aminopropyl)amino]-N-hydroxyhexanamide (15), has an apparent Ki of 0.001 microM. It binds to the target enzyme 11,000 times tighter than the substrate (apparent Km = 11 microM). These compounds and a previously reported series of compounds (Dredar, S. A.; Blankenship, J. W.; Marchant, P. E.; Manneh, V. A.; Fries, D. S. J. Med. Chem. 1989, 32, 984-989) are useful in mapping the active site and determining the physiological function of N8-AcSpd deacetylase.

A series of five epimeric pairs of naltrexone derivatives that contain an electrophilic substituent at the 6 alpha- or 6 beta-position was synthesized and tested on the guinea pig ileal longitudinal muscle (GPI) and mouse vas deferens (MVD) preparations in order to determine if the orientation of the electrophile is important for covalent bonding to opioid receptors. In the GPI all compounds were pharmacologically active as reversible agonists, but only the 6 beta-isomers of the fumaramate ester 2b (beta-FNA) and isothiocyanate 6b exhibited covalent reactivity, involving a selective irreversible antagonism of the mu agonist, morphine, without affecting kappa agonists. The 6 alpha-isomer 2a (alpha-FNA) was itself nonalkylating but was able to protect the GPI against alkylation by its epimer, beta-FNA, indicating that the two epimers bind to the same receptor. These results suggest that the proper orientation of the electrophilic substituent is required for covalent bonding with a proximal nucleophile in the case of mu receptor blockade. Moreover, the lack of covalent bonding to kappa receptors by these or other ligands in this series indicates the possible absence of sufficiently reactive nucleophiles on this recognition site. In the MVD, 2b, but not 2a, irreversibly antagonized morphine (as in GPI), whereas neither epimer exhibited irreversible antagonism toward the delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE). In contrast, both of the isothiocyanate epimers (6a,b) irreversibly blocked mu and delta receptors. Evidence suggesting differences between mu receptors in the MVD and GPI was obtained with the beta-iodoacetamide 5b, which was an irreversible blocker of morphine only in the MVD. When analyzed together with those of previous studies with the nitrogen mustard analogues, alpha- and beta-chlornaltrexamine, the data suggest that the receptor-alkylating ability of each isomer in an epimeric pair differs most when the electrophile possesses a narrow spectrum of reactivity.

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Analogues of N8-acetylspermidine (1) were synthesized as potential inhibitors of the cytoplasmic enzyme N8-acetylspermidine deacetylase. The compounds were assayed for their ability to inhibit the deacetylation of 1 in a cytosolic fraction from rat liver. The apparent Ki values were determined by Dixon plots. The apparent Km of 1 for this enzyme is 11.0 microM. It was found that compounds which lacked the N1 or the N4 of spermidine were less effective at competing for the enzyme than the substrate. All compounds with acyl substituents larger than acetyl were less potent inhibitors than the corresponding acetylated derivatives. Thus, the enzyme's selectivity as a deacetylase seems to be attributable to steric hindrance which occurs with larger acyl groups. The N8 of the substrate is not essential for its binding to the enzyme. Replacement of N8 with a CH2 group gives the ketone 14, which has an apparent Ki of 0.18 microM, 60-fold lower than the apparent Km of 1. The inhibitory potency of 14 is retained in compounds substituted at the N1 position. The N1,N1-dimethyl and the N1,N1-diethyl analogues (15 and 16) of 14 have apparent Ki values of 0.096 and 0.10 microM, respectively. These agents are the most potent inhibitors of N8-acetylspermidine deacetylase reported, and they are promising tools for use in determining the physiological function of N8-acetylspermidine deacetylation.

The chapter provides coverage of all drugs currently used for the treatment of human African trypanosomiasis (African sleeping sickness), American trypanosomiases (Chagas' disease), and leishmaniasis. Collectively, this group of diseases is caused by flagellated protozoan of the order Kinetoplastida. The drugs currently used to treat these diseases include melarsoprol, suramin, pentamidine, organic antimonials, and several nitroheterocyclic agents. The agents have all been in use for 25–75 years. They have a high degree of toxicity and the first four in the preceding list must be given by parenteral injection over a 2‐ to 6‐week time period. Tolerance has developed to most of the drugs in at least some geographical areas. Eflornithine is the only agent approved in the last 50 years for the treatment of African trypanosomiasis, although it is expensive, requires prolonged systemic dosage, and is effective only against T. brucei gambiense . Megazol, trybazine, DB289, and CGP 40215A have all yielded encouraging results in in vivo preclinical studies against African trypanosomiasis. All four of these agents have entered or are scheduled to enter clinical trials. Nifurtimox and benznidazole are the only agents approved to treat Chagas' disease. The agents are toxic, rarely produce long‐term cures, and resistance to them has developed. The third‐generation triazole antifungal agents posaconazole and UR‐9825 have given encouraging preclinical results against Chagas' disease. Meltefosine has been found to be orally active and to produce 98% cure rates of visceral leishmaniasis. New classes of experimental antitrypanosomal agents include the bisphosphonates, which disrupt lipid metabolism, and cysteine protease inhibitors. Agents from both of these mechanistic classes are being advanced as potential antitrypanosomal agents. Kinetoplastid biochemistry offers numerous opportunities for the development of chemotherapeutic agents having a high degree of selective toxicity. Trypanothione, the N 1 , N 8 ‐bis(glutathionyl)spermidine metabolite that replaces glutathione in redox protection reactions in kinetoplastids, is one hopeful target for drug design. A second possible target is the kinetoplastid organelle named the glycosome. African trypanosomes and perhaps other kinetoplastids are highly dependent on glycolysis for energy production. Enclosing the enzymes for glycolysis in glycosomes increases the efficiency of glycolysis compared to its rate in mammalian cells. Any potent inhibitor of an enzyme contained in the glycosome, or of any of the biochemical processes associated with glycosomal function, might be an effective drug against these parasites.