Human dihydroorotate dehydrogenase (huDHODH) is essential for de novo biosynthesis of pyrimidines and the target of two immunosuppressive drugs, brequinar and the leflunomide metabolite A77-1726 (Chen et al., 1992; Davis et al., 1996). Using a T7 RNA polymerase expression system, we produced huDHODH as a fusion protein containing an amino-terminal decahistidine tag. Escherichia coli growth and ...

Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure-activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by 11, 18, and 21. For example, 11 possesses a dissociation constant (K(d)) for BMK1 of 19 nM, a cellular IC(50) for inhibiting epiderma...

A novel series of 3-(2-amino-6-pyrimidin-4-yl)-6-bromo-2H-chromen-2-one (5a-5j) were synthesized from 3-acetyl-6-bromo-2H-chromen-2-one (3). The structures of the synthesized compounds were elucidated by IR, H-NMR, C-NMR, and mass spectroscopic techniques. The synthesized compounds were screened for in-vivo analgesic activity at a dose of 20 mg/kg body weight. Among them, compounds 5a, 5b and 5...

A number of chalcones were synthesized by reacting indole-3-aldehyde, prepared by Vilsemeir Haack reaction with 4-substituted acetophenone in NaOH solution in ethanol. These chalcones were immediately reacted with urea, thiourea and guanidine hydrochloride in presence of concentrated hydrochloric acid as reagent to obtain the corresponding hydroxy, thio and amino pyrimidines. The synthesized he...

Despite more than 50 years of effort, the origin of the genetic code remains enigmatic. Among different theories, the stereochemical hypothesis suggests that the code evolved as a consequence of direct interactions between amino acids and appropriate bases. If indeed true, such physicochemical foundation of the mRNA/protein relationship could also potentially lead to novel principles of protein...

Many critical processes in the cell involve direct binding between RNAs and proteins, making it imperative to fully understand the physicochemical principles behind such interactions at the atomistic level. Here, we use molecular dynamics simulations and 15 μs of sampling to study the behavior of amino acids and amino acid sidechain analogs in high-concentration aqueous solutions of standard RN...

We have previously reported on the tumor inhibitory properties of 5-fluorouracil and 5-fluoroorotic acid (3, 4), prepared by Duschinsky et al. (5), and on the initial clinical trials of 5fluorouracil with patients with far advanced solid tumors (6). The metabolism of 5-fluorouracil and 5-fluororotic acid has been studied, data on excretion and tissue distribution in mice and man have been repor...