Clofarabine is a promising DNA polymerase inhibitor currently
in clinical trials for a variety of liquid and solid tumor
indications. The efforts for development of a new manufacturing
process for clofarabine are presented. This new process allows
for the reliable and efficient production of drug substance in
high anomeric excess and high overall purity, without using
chromatography. The high anomeric selectivity is achieved by
reacting 2-chloroadenine with 1-bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-d-ribofuranose (4) and potassium ter
t-butoxide
in a mixture of three solvents. Following crystallization, anomeric ratios exceeding 50 (β/α) are achieved. Deprotection and
additional crystallization afford a clofarabine drug substance
containing less than 0.1% of the α-anomer.
Matrix isolation infrared spectroscopy has been combined with MP2/6-31+G(d,p) calculations to characterize the 1:1 hydrogen-bonded complexes between H 2 O 2 and the bases NH 3 and N(CH 3 ) 3 . Most obvious from the spectra of these complexes and their deuterated analogues is the shift to lower frequency of the hydrogenbonded O-H or O-D stretching bands relative to the isolated monomers. The experimental shifts are in good agreement with the computed shifts. Perturbation of the O-O-H bending mode was also observed, along with shifts of certain vibrational modes of the base subunits in the complexes. Surprisingly, the experimental intensities of the product bands are low when compared to other hydrogen-bonded systems and to the computed intensities.
Tethering Dol15 via partially reduced disulfide bonds at the drug C-terminus via a non-cleavable linker (trastuzumab-MC-C-term-Dol15) resulted in an equally effective ADC in vitro, showing that site of antibody conjugation did not influence ADC activity. However, tethering Dol15 at the drug N-terminus using non-cleavable and cleavable linkers (trastuzumab-MC-N-term-Dol15 and trastuzumab-MC-VC-PABC-N-term-Dol15, respectively) resulted in ineffective ADCs. Thus, Dol15 tethered at the C-terminus may be a useful tubulin-targeting agent for conjugation at various antibody reactive sites.
Matrix isolation infrared spectroscopy has been combined with MP2/6-31+G(d,p) and MP2/aug′-cc-pVTZ calculations to characterize the 1:1 hydrogen-bonded complexes between H 2 O 2 and bases containing phosphorus and sulfur as electron pair donor atoms. Most obvious from the spectra of the complexes HOOH:PH 3 , HOOH: P(CH 3 ) 3 , HOOH:SH 2 , and HOOH:S(CH 3 ) 2 and their deuterated analogues is the shift to lower frequency of the hydrogen-bonded O-H or O-D stretching bands (ν s ) relative to isolated H 2 O 2 and D 2 O 2 . The experimental shifts are in good agreement with the computed shifts. Shifted modes of both H 2 O 2 and base subunits have been observed, along with the band for the intermolecular librational mode of each complex. Comparisons are made between the structures and spectral properties of these complexes and related complexes formed between H 2 O 2 and corresponding N and O bases.
Matrix isolation infrared spectroscopy has been combined with MP2/aug′-cc-pVDZ calculations to characterize the 1:1 hydrogen-bonded complexes between H 2 O 2 and the hydrogen halides HF, HCl, and HBr. The infrared spectra of the these complexes are characterized by an intense, red-shifted H-X stretching band, as well as slight perturbations to several of the HOOH vibrational bands. For the HF complex, the intermolecular librational modes were also observed. The ab initio calculations identified two equilibrium structures on each surface, one an open structure, and the other cyclic. These two structures have similar binding energies. However, only the open structure appears to be present in argon and nitrogen matrices. This open structure is preferentially stabilized by interaction of its larger dipole moment with the matrix medium.
Within the last few decades, increases in computational resources have contributed enormously to the progress of science and engineering (S & E). To continue making rapid advancements, the S & E community must be able to access computing resources. One way to provide such resources is through High-Performance Computing (HPC) centers. Many academic research institutions offer their own HPC Centers but struggle to make the computing resources easily accessible and user-friendly. Here we present SHABU, a RESTful Web API framework that enables S & E communities to access resources from Boston University's Shared Computing Center (SCC). The SHABU requirements are derived from the use cases described in this work.
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