Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin-based drugs are still nowadays limited to antagonists of vitamins B9 and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin-based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B9 and B12 .

This communication describes the anti-platelet effects of a new class of cis-rhenium(II)-dicarbonyl-vitamin B 12 complexes with tuneable CO releasing properties.Carbon-monoxide releasing molecules (CORMs) represent an innovative class of compounds which attract interest due to their potential therapeutic utility. Unlike most common drugs whose pharmacological action is dependent on their interaction with a macromolecular target and whose potency is dictated by the stability of the drug-target complex, CORMs exert their therapeutic action via the liberated CO molecules. [1][2][3][4][5] However, apart from the common scientific consensus that CORM-based therapy should not lead to significant carboxyhemoglobin (COHb) formation and to the inhibition of respiratory enzymes that are sensitive to CO, it is questionable whether CORMs should release CO slowly or rapidly and what kinetics of CO release is most advantageous for therapeutic applications. There are only few reports clearly showing the advantages of CORMs slowly releasing CO over those releasing CO instantly 6,7 and they relate to the anti-platelet effects of CORMs. Furthermore, it has proved chemically challenging to fine-tune the activation and the rate of CO release within a family of structurally similar CORM compounds. For all of these reasons, versatile classes of CORMs with tuneable release properties affording anti-platelet activity are highly desired for tackling these open questions in systematic structure-activity relationship studies. Such studies will facilitate the development of CORMs with optimal antiplatelet activity. -(CO) 2 fragment. This approach seemed to be reasonable because small variations in the coordination sphere of rhenium complexes have profound consequences on the electrochemistry, water stability and CO releasing properties of the dicarbonyl core.17 B 12 appeared to be attractive as ligand for the rhenium-based CORM entity mainly because of two reasons: (a) its cellular uptake properties can be exploited to deliver therapeutic agents specifically at disease sites; 18-20 (b) the electronic properties at the cobalt center can be selectively modified by introducing structural modifications at the corrin-p-system. 21-24Having the general design of the B 12 -ReCORMs derivatives in mind (Scheme 1), we synthesized and studied first a series of Scheme 1 General design concept for the tuneable activation of CORMbiovectors conjugates.

F430 is au nique enzymatic cofactor in the production and oxidation of methane by strictly anaerobic bacteria. The key enzyme methyl coenzyme Mreductase (MCR) contains ahydroporphinoid nickel complex with acharacteristic absorption maximum at around 430 nm in its active site.H erein, the three-step semisynthesis of ahybrid Ni II -containing corrinoid that partly resembles F430 in its structural and spectroscopic features from vitamin B 12 is presented. Ak ey step of the route is the simultaneous demetalation and ring closure reaction of a5 ,6-secocobalamin to metal-free 5,6-dihydroxy-5,6-dihydrohydrogenobalamin with cobaltocene and KCN under reductive conditions.Studies on the coordination chemistry of the novel compound support an earlier hypothesis why nature carefully selected ac orphin over acorrin ligand in F430 for challenging nickel-catalyzed biochemical reactions.

The synthesis of vitamin B in four steps from an artificial green secocorrinoid is presented. The stereospecific reconstitution of the B-ring of the cobalamin involves a quantitative and rapid ligand-centered radical ring closure reaction leading first to a new B derivative with antivitamin activity that is subsequently converted to the natural product. Chemoselectivity in the one-electron reduction of the macrocycle was achieved by introducing inorganic cyanide as an axially coordinating protecting group of the otherwise reduction-sensitive Co-ion. The integrity of structure and function of the reconstituted natural product was unequivocally proven by single crystal structural analysis and a microbiological assay using Lactobacillus leichmannii.

A synthetic route toward B ring opened 7,8-seco-cyanocobalamins is described. Hydrolysis of a novel c-lactone vitamin B12 (B12) derivative generates a cobalamin (Cbl) with a β-bromo alcoholate subunit that reacts in situ via Grob fragmentation to the secocorrin.

F430, ein einzigartiger enzymatischer Kofaktor,ist an der Bildung und Oxidation von Methan in streng anaeroben Bakterien beteiligt. Das Schlüsselenzym Methyl-Koenzym-M-Reduktase (MCR) weist in seinem aktiven Zentrum einen porphinoiden Nickel-Komplex auf, der ein charakteristisches Absorptionsmaxi-Abbildung 1. Vergleich der Strukturformeln (oben) sowie der Kernstrukturen (unten) von Vitamin B 12 und Aquocobalamin (1 und 1-OH 2 + ,G egenion nicht gezeigt), Koenzym F430 sowie dem neuen Ni II -Porphinoid 4.

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BECAUSE of the relatively small variation in the mature bodyweight of stallions and bulls, testicular size standards do not routinely relate to bodyweight. However, in dogs there may be a 10-fold variation in mature bodyweight and a high correlation between testicular weight and bodyweight has been shown (Woodall and Johnstone 1988a). Therefore, when evaluating if testicular size is normal for a dog, consideration must also be given to bodyweight, especially since one study found no differences between the weights of left and right canine testes (Zong-Han 1998). Therefore, the aim of this study was to gather and collect data concerning testicular weights, epididymal weights and bodyweights for the domestic dog (Canisfamiliaris).Twenty-nine adult intact male dogs of various breeds and of unknown health or breeding history were obtained from a local animal shelter after euthanasia. They were selected on the basis of their mature phenotype. Their canine teeth were examined, and only those with permanent canine teeth were included in the study. The scrotum of each dog was examined to ensure the presence of two scrotal testes. Each dog was weighed and the testes of each dog were removed. The epididymides were carefully dissected from the testes and the testes were then weighed separately on a balance, accurate to within 10 mg. All measurements were concluded within 10 minutes of testicular excision. Means (se) and coefficients ofvariation were calculated for each variable using standard procedures. Statistical comparisons were undertaken using the Student's t test.The dogs used in this study showed a 10-fold range in body mass, 5-5-fold range in testicular weight and 10-fold range in epididymal weight (Table 1). The mean (se) bodyweight was 15-4 (1.9) g. The mean weight of the right testes was 9*93 (0.9) g and weight of the left testes was 9 94 (1-0) g.The difference in weight between the right and left testes was not statistically significant. Similarly, there were no differences in weight between the right and the left epididymides (2-02 [0-2] g for both). The value for testes as a percentage of body mass was 0-13. A high correlation, however, was found between testicular weight and bodyweight (r=0-88); epididymal weight and bodyweight (r=0.80), and between epididymal weight and testicular weight (r=0-88). The statistical significance was P<0-001 for all the correlation coefficients.A functional relationship between the relative size of testes and requirements for sperm production has been demonstrated in a comparative survey of primate species (Harcourt and others 1981). It appears that testes are relatively large in primates and other mammals which have promiscuous mating systems where copulatory frequency is high and, where copulation is infrequent (monogamy system), the testes are small. Kenagy and Trombulak (1986) also indicated that a relationship between mating system and size of testes could possibly be generalised for some groups of mammals. The seven wild carnivores for which they obtained data (fox [Vulpe...