Natural products are potential sources of
lead compounds, especially intractable chemotherapeutic targets that require
molecules with three-dimensional diversity rather than flatter “drug-like”
molecules. This review article highlights the author’s efforts toward
establishing synthetic routes to natural anti-tuberculosis and anti-tumor
products, including structure−activity relationship
studies. The synthetic targets, caprazamycin C, intervenolin, and leucinostatin
A, exhibit striking biologic properties, such as antibacterial activity toward
highly resistant strains of tuberculosis and interference with growth signals
from stromal cells to tumor cells.
The author developed a series of vitamin D
analogues which act as agonist, partial agonist, or antagonist for vitamin D
receptor (VDR). The author examined the structures of the ligand-binding domain
(LBD) of VDR complexed with the analogues by the X-ray crystal structural
analysis, and small-angle X-ray scattering analysis combined with molecular
dynamics simulation. All states of the VDR-LBD, which include agonist-, partial
agonist- and antagonist-binding structures and apo-state structure, were clarified.
Thus the author elucidated the mechanisms of VDR agonism, partial agonism, and antagonism
based on structural changes (differences) in VDR-LBD induced by ligand binding.
The novel progesterone receptor antagonists based on the multi-template approach were developed. Multi-template strategy enables facile structure-activity relationship (SAR) investigation, and phenylamino-1,3,5-triazine scaffold is a useful core structure for development of transcription modulators targeting nuclear receptors.
Light controllable compounds are very useful tools to manipulate biological signaling. In this paper, authors showed the biological applicability of a yellowish-green light controllable NO releaser, NO-Rosa5, which is more readily synthesizable and efficient NO releaser than its prototype, NO-Rosa1. NO-Rosa5 showed less toxicity in MTT assay than a blue light controllable NO releaser, NOBL-1, and was applicable to photoinduced NO release control in cellular condition. Furthermore, NO-Rosa5 could control vasodilation of rat aortic strip by light stimulation in Magnus test condition. NO-Rosa5 is expected to be useful chemical tool for NO research and utilized for innovative therapeutic method.
The aim of this study was to demonstrate the usefulness of T2 measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. In the course of the experiments, the authors found that T2 measurements could detect the difference between the amorphous and crystalline API; furthermore, it was effective in monitoring the transformation from amorphous to crystalline during a thermal stress test. From these findings, the authors concluded that T2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.
Although fluorine-containing aryl formates have currently flourished as pharmaceutical and agrochemical intermediates, there is limited number of bearable methods in a large scale synthesis. In this article, the authors developed new operationally secure preparation method for dichloromethyl alkyl ethers having long carbon chains, and direct formylation of fluorine-containing aromatics with those reagents, which are applicable in a large scale synthesis. The authors also showed a number of examples for O-formylation of fluorine-containing and non-fluorine-containing aromatics with those reagents and the mechanistic aspect was discussed. The present method is simple and straightforward for laboratory and industrial use.
This paper describes that the first total synthesis of 3-epi-Juruenolide C. The γ-lactone natural product, which was isolated from roots of Virola surinamensis, exhibits moderate antifungal activity against Cladosporium cladosporioides. The synthesis features a highly selective cross metathesis and the subsequent one-pot regioselective bromination, an intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel, and a face-selective hydrogenation using a homogeneous Wilkinson’s catalyst. The sequential synthetic procedures could be useful to complete the synthetic and biological studies of other related γ-lactone natural products.
Regioselective cyanation of simple and non-activated carbon–carbon bonds catalyzed by nickel complexes is described. This protocol enables to use of the substituted allenes for regio- and stereocontrolled transformations and their applications for cyclization, 3-component coupling reaction, heterocycle formation as well as natural product synthesis are demonstrated. The author reveals the origin of the above selectivity by axial chirality transfer process using optically active allenes as substrates. Steric bulk of substituents is found to be a key factor for discrimination of allenyl carbon–carbon double bonds in hydrometallation step.
This paper describes the development and validation of a method for measuring linezolid and its metabolites PNU-142300 and PNU-142586 in human plasma, using ultra-performance liquid chromatography (UPLC) method. This method enables the simultaneous measurement of these three components within 3 min. Further, plasma concentrations of linezolid, PNU-142300 and PNU-142586 in patients treated with linezolid could be measured. The developed method is a useful tool for therapeutic drug monitoring and clinical pharmacokinetic/pharmacodynamic (PK/PD) profiling of linezolid, as well as for dose optimization during treatment.
3-Alkenyl cephem compound is a pharmaceutical intermediate. It is typically crystalized by pH adjustment method. However, since the filtration time in the solid-liquid separator is a bottleneck in the production, there is a need to control crystal morphology while changing the pH. This study could be shorten filtration time by pH-modulation operation that repeating the crystallization operation in the vicinity of solubility. The obtained monodisperse particles were like a pseudo-growth body in which a large number of primary particles were aggregated and increased, rather than being a crystallite growth.
Surugamide A, a non-ribosomal peptide with cathepsin B inhibitory activity, and its closely related derivatives, surugamides B-E are cyclic octapeptides produced by several Streptomyces species. All these peptides except for surugamide B contain a D-Ile residue that involve Cβ-epimerization step during its biosynthesis. However, the genes responsible for this conversion is absent in the biosynthetic gene cluster of surugamides. To clarify this issue, surugamide A containing D-Ile as well as its epimer having D-allo-Ile were synthesized. HPLC and Marfey’s analyses showed that surugamide A actually possesses D-allo-Ile instead of D-Ile, requiring structural collection of this group of peptides.
In order to maximize the effect of drugs,
nanomedicines, drug-containing nanoparticles, have become popular in the field
of medicine as they allow selective delivery of drugs to the disease target. It
is important to understand the drug release form nanomedicine at the disease
target. In this study, the authors developed a
simple and easy method of monitoring drug release from nanomedicine using a
fluorescence analysis, especially fluorescence fingerprint. The authors used DOXIL as a typical nanomedicine and
found out that the release of the encapsulated drug, doxorubicin, is
accelerated by albumin which is the most abundant protein in the blood.
A person may choose to wear an accessory so as to
enhance their appearance and give them confidence and thus a change of
character. So what happens when accessories are decorated with drugs? The
author has developed molecular accessories for drugs through supramolecular
chemistry to create new medicines and pharmaceutical technologies. In this article,
the author introduces cyclodextrin-based supramolecular accessories such as molecular
necklace, molecular earring, and intelligent molecular necklace, and describes
their application in pharmaceutical sciences. Moreover, the author proposes a new
concept in pharmaceutical sciences termed as “supramolecular pharmaceutical sciences,” which combines
pharmaceutical sciences and supramolecular chemistry.
Wet granulation is one of the fundamental
unit operations for manufacturing pharmaceutical solid dosage forms including
tablets. This study investigated in detail the states of water incorporated in
wet granules composed of different fillers. The key instrument to evaluate the
state of water was a low-field benchtop 1H-NMR time-domain NMR
(TD-NMR). This study successfully concluded that the state of water
significantly affected the wet granulation process and the characteristics of
the resultant granules. The findings can offer valuable knowledge on wet
granulation process from the viewpoint of molecular mobility of water.
A number of clinical trials demonstrated that
tigecycline was effective and well tolerated in the treatment of patients with
various bacterial infections, but few literatures had shown the coagulopathy
induced by tigecycline. The retrospective analysis in this paper to assess the impact of tigecycline on
coagulation parameters in 50 patients showed that the plasma fibrinogen (FIB)
level decreased during treatment, which was statistically significant (P < 0.001). The mean values of
activated partial thromboplastin time (aPTT) and prothrombin time (PT) were
significantly increased, respectively. It is
necessary for practitioners routinely monitor coagulation level in at-rick
patient populations treated with tigecycline.
When a neutral solution of a nucleoside
mixture was irradiated with UV light having wavelength longer than 300 nm,
addition of salicylic acid to the solution greatly accelerated the reaction of
thymidine. The UV light irradiation of thymidine solution in the presence of
salicylic acid generated isomers of cyclobutane thymidine dimers almost
exclusively. UV irradiation with the longer wavelength of 350 nm induced almost
no reaction. The results indicate that salicylic acid is a photosensitizer for
thymidine dimerization excited by UV light of wavelength 300 to 350 nm.
“Chocolet” is an orally disintegrating tablet formulated with cocoa powder to
mask the bitterness of drugs. The name “Chocolet” indicates that the
formulation combines the good taste of chocolate
with the ease of taking of an orally disintegrating tablet. Rebamipide chocolet has been prepared with excellent
palatability properties, which could not be achieved using a sweetener alone,
by using the combination of a sweetener and cocoa powder as an agent for
masking bitterness. “Chocolet” can be used to provide patient-friendly tablets, thus helping to improve medication adherence.
Isoschizogamine is a member of the schizozygane family of indole
alkaloids. Its highly fused hexacyclic structure containing an aminal adjacent
to a quaternary stereocenter makes it a challenging synthetic target. While the authors reported the total synthesis of
(–)-isoschizogamine in 2012, this paper describes an alternative preparation of
their pivotal synthetic intermediate. The synthesis features a stereoselective
construction of a quaternary carbon by the Claisen-Johnson rearrangement and a
stereoselective rhodium-mediated 1,4-addition of arylboronic acid. The
reliability of this synthetic route enables a
sufficient supply of the intermediate for the total synthesis of isoschizogamine.
of repeatability in supercritical fluid chromatography with electrochemical
detection (SFC-ECD) system is necessary to construct an SFC-ECD as a
quantitative method with satisfactory precision. This article is the first report that a
method for the assessment of repeatability in SFC-ECD has been proposed by
means of the ISO 11843 part 7 which can theoretically provide detection limits
and standard deviation (SD) through the stochastic properties of baseline noise
without repetitive measurements of real samples. The present method is practically useful,
and both experimental time and chemicals can be saved to estimate the
repeatability in SFC-ECD.
A series of 8-methoxy or
8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole
derivatives at the C-7 position was synthesized, and the pharmacological,
physicochemical, and toxicological properties of the individual compounds were
evaluated. Novel 7-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-8-methylquinolone
7 exhibited potent and better activity than
LVFX and MFLX against streptococci, staphylococci, enterococci, E. coli, A. baumannii, and anaerobes. Compound 7 also demonstrated favorable
pharmacokinetic and pharmacodynamic properties and an acceptably safe
toxicological profile. Consequently, compound 7 was selected as a clinical candidate for further evaluation as a new-generation,
broad-spectrum quinolone antibiotic. Compound 7 is expected to become an option for antibacterial therapy against multidrug-resistant A.