Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. ...When incubated with rat, dog, monkey, and human liver microsomes, (14)Claromustine was converted to 90CE (C-8) and seven other radioactive components (C-1-C-7). There was little difference in the metabolite profile among the species examined, in part because the formation of most components (C-1-C-6 and 90CE) did not require NADPH but involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Laromustine caused direct inhibition of CYP2B6 and CYP3A4/5 (the two enzymes involved in C-7 formation) as well as of CYP2C19. K(i) values were 125 microM for CYP2B6, 297 muM for CYP3A4/5, and 349 microM for CYP2C19 and were greater than the average clinical plasma C(max) of laromustine (25 microM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6, and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 microM laromustine did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, but the highest concentration of laromustine decreased the activity and levels of immunoreactive CYP3A4. The results of this study suggest the laromustine has 1) negligible victim potential with respect to metabolism by cytochrome P450 enzymes, 2) negligible enzyme-inducing potential, and 3) the potential in some cases to cause inhibition of CYP2B6, CYP3A4, and possibly CYP2C19 during and shortly after the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant.
As a by-product of high-precision, ultradeep stellar photometry in the Galactic globular cluster NGC 6397 with the Hubble Space Telescope, we are able to measure a large population of background ...galaxies whose images are nearly pointlike. These provide an extragalactic reference frame of unprecedented accuracy, relative to which we measure the most accurate absolute proper motion ever determined for a globular cluster. We find k sub(a) cos d = 3.56 c 0.04 mas yr super(-1) and k sub(d) = -17.34 c 0.04 mas yr super(-1). We note that the formal statistical errors quoted for the proper motion of NGC 6397 do not include possible unavoidable sources of systematic errors, such as cluster rotation. These are very unlikely to exceed a few percent. We use this new proper motion to calculate NGC 6397's UVW space velocity and its orbit around the Milky Way and find that the cluster has made frequent passages through the Galactic disk.
The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since ...deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R1, which contains polythiols and R2, which contains non-heme iron and a free tyrosyl radical. Both the R1 and R2 subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs α-(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP, which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
The ACS Survey of Galactic globular clusters is a Hubble Space Telescope Treasury program designed to provide a new large, deep, and homogeneous photometric database. Based on observations from this ...program, we have measured precise relative ages for a sample of 64 Galactic globular clusters by comparing the relative position of the clusters' main-sequence (MS) turnoffs, using MS fitting to cross-compare clusters within the sample. This method provides relative ages to a formal precision of 2%-7%. We demonstrate that the calculated relative ages are independent of the choice of theoretical model. We find that the Galactic globular cluster sample can be divided into two groups-a population of old clusters with an age dispersion of ~5% and no age-metallicity relation, and a group of younger clusters with an age-metallicity relation similar to that of the globular clusters associated with the Sagittarius dwarf galaxy. These results are consistent with the Milky Way halo having formed in two phases or processes. The first one would be compatible with a rapid (<0.8 Gyr) assembling process of the halo, in which the clusters in the old group were formed. Also these clusters could have been formed before re-ionization in dwarf galaxies that would later merge to build the Milky Way halo as predicted by CDM cosmology. However, the galactocentric metallicity gradient shown by these clusters seems difficult to reconcile with the latter. As for the younger clusters, it is very tempting to argue that their origin is related to their formation within Milky Way satellite galaxies that were later accreted, but the origin of the age-metallicity relation remains unclear.
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