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Abstract: We recently reported that 22S-butyl-1α,24R-dihydroxyvitamin D3 3 recovers the agonistic activity for vitamin D receptor (VDR), although its 25,26,27-trinor analog 2 is a potent VDR antagonist. To investigate the structural features involved in the recovery of agonism, we crystallized the ternary complex of VDR-ligand-binding domain, ligand 3 and coactivator peptide, and conducted X-ray crystallographic analysis of the complex. Compared with the complex with 2, the complex with 3 recovered the following structural features: a pincer-type hydrogen bond between the 24-hydroxyl group and VDR, the conformation of Leu305, the positioning of His301 and His393, the stability of the complex, and intimate hydrophobic interactions between the ligand and helix 12. In addition, we evaluated the potency of both compounds for recruiting RXR and coactivator. The results indicate that the complex with 3 generates a suitable surface for coactivator recruitment. These studies suggest that the action of 2 as an antagonist is caused by the generation of a surface not suitable for coactivator recruitment due to the lack of hydrophobic interactions with helix 12 as well as insufficient hydrogen bond formation between the 24-hydroxyl group and VDR. We concluded that the action of 3 as an agonist is based on the elimination of these structural defects in the complex with 2. [ABSTRACT FROM AUTHOR]

Abstract: The active form of vitamin D3, 1α,25-dihydroxyvitamin D3(1α,25(OH)2D3), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)2D3 therapeutic potential in treating cancers, numerous analogues have been synthesized with an attempt to increase anti-proliferative and/or decrease calcemic properties. Among these analogues, 19-nor-1α,25(OH)2D2 while being less calcemic has equivalent potency as 1α,25(OH)2D3 in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3 (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)2D3 in inhibiting the proliferation of an immortalized normal prostate PZ-HPV-7 cells and the invasion of androgen insensitive PC-3 prostate cancer cells, respectively. In this study, we further investigated the effects of MART-10 and 1α,25(OH)2D3 on the dose- and time-dependent induction of CYP24A1 gene expression in PC-3 prostate cancer cells. We found that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared to 1α,25(OH)2D3, suggesting that MART-10 is less susceptible to CYP24A1 degradation. Molecular docking model of human CYP24A1 and MART-10 indicates that its side chain is far away from the heme ion and is less likely to be hydroxylated by the enzyme. Furthermore, MART-10 was a more potent inhibitor of PC-3 cell proliferation and invasion compared to 1α,25(OH)2D3. In addition, MART-10 down-regulated matrix metalloproteinase-9 (MMP-9) expression which could be one mechanism whereby MART-10 influences cancer cell invasion. Finally, we observed that subcutaneous administration of MART-10 up-regulated the CYP24A1 mRNA expression in rat kidneys without affecting their plasma calcium levels. Thus, our findings demonstrate that MART-10 is biologically active in vivo and may be an effective vitamin D analogue for clinical trials to treat prostate cancer. [Copyright &y& Elsevier]

The potency of 25-hydroxyvitamin D3 (25(OH)D3) is increased by several fold through its metabolism into 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) by cytochrome P450 27B1 (CYP27B1). Thus, the pivotal role of 1α-hydroxylation in the activation of vitamin D compounds is well known. Here, we examined the metabolism of 25-hydroxy-16-ene-23-yne-vitamin D3 (25(OH)-16-ene-23-yne-D3), a synthetic analog of 25(OH)D3 in a cell-free system and demonstrated that 25(OH)-16-ene-23-yne-D3 is neither activated by CYP27B1 nor inactivated by cytochrome P450 24A1 (CYP24A1). These findings were also confirmed in immortalized normal human prostate epithelial cells (PZ-HPV-7) which are known to express both CYP27B1 and CYP24A1, indicating that the structural modifications featured in 25(OH)-16-ene-23-yne-D3 enable the analog to resist the actions of both CYP27B1 and CYP24A1. To provide intelligible structure-function information, we also performed molecular docking analysis between the analog and CYP27B1. Furthermore, 25(OH)-16-ene-23-yne-D3 was found to suppress the growth of PZ-HPV-7 cells with a potency equivalent to 1α,25(OH)2D3. The antiproliferative activity of 25(OH)-16-ene-23-yne-D3 was found to be vitamin D receptor (VDR)-dependent as it failed to inhibit the growth of mammary tumor cells derived from VDR-knockout mice. Furthermore, stable introduction of VDR into VDR-knockout cells restored the growth inhibition by 25(OH)-16-ene-23-yne-D3. Thus, we identified 25-hydroxy-16-ene-23-yne-vitamin D3 as a novel non-1α-hydroxylated vitamin D analog which is equipotent to 1α,25(OH)2D3 in its antiproliferative activity. We now propose that the low potency of the intrinsic VDR-mediated activities of 25(OH)D3 can be augmented to the level of 1α,25(OH)2D3 without its activation through 1α-hydroxylation by CYP27B1, but by simply preventing its inactivation by CYP24A1., (© 2014 Wiley Periodicals, Inc.)

Owing to the Japanese healthcare system reform, the place where patients receive medical care is beginning to shift from hospital to home. This study aims to evaluate the usefulness of sharing medication-related reviews through a questionnaire survey and hospital pharmacist intervention survey. It appears that almost all community pharmacists have inadequate information at the time of dispensing medication to, monitoring adverse effects of, and counseling cancer patients. There is no doubt that hospital pharmacists should provide more information to community pharmacists at conference prior to discharge. Fortunately, at the Tokyo Women's Medical University Hospital, hospital pharmacists and community pharmacists work closely to contribute to an effective patient care at discharge. Thus, there is an urgent need to ensure greater cooperation between hospital pharmacists and community pharmacists in Japan.

Erymelanthine 1 and 8-oxoerymelanthine 2 are unique erythrina alkaloids containing a pyridine ring. We synthesized (+/-)-8-oxoerymelanthine 2 in 2.0% overall yield using the following key reactions. The characteristic 6-5-6-6-membered ring system was constructed by the stereoselective intermolecular Diels-Alder reaction. Oxidative cleavage of the aromatic D-ring was conducted chemo- and regioselectively by ozonolysis in the presence of BF(3)-etherate. This cleavage site is identical to the site cleaved during the biosynthesis of erymelanthine 1. Nitrogen incorporation was achieved by aminolysis. Conversion of the D-ring pyridone to the corresponding pyridine was efficiently accomplished by palladium-catalyzed reduction of aryl triflate 21. This is not only the first total synthesis of (+/-)-8-oxoerymelanthine 2 (where the D-ring is pyridine) but also, more importantly, a biomimetic total synthesis of an erythrinan D-aza alkaloid.

To examine the influence of drug therapy guidance by pharmacists on the use of a rescue dose (RD) for opioid analgesics (opioids) and pain as well as drug therapy guidance in cancer pain treatment, we conducted a patient satisfaction survey. The subjects were 56 cancer patients undergoing opioid therapy in hospitals belonging to the Symptom Control Research Group (SCORE-G). The survey period was 2 months (from November 1 until December 31, 2006). Drug therapy guidance regarding the use of RD was performed twice in each patient to evaluate the patients' satisfaction. RD was prescribed in 87.8% of the patients in the first guidance and in 80.5% in the second guidance periods. The proportion of patients who used RD significantly increased from 63.8% to 87.5%. Five items significantly improved in the second guidance period: "marked analgesic effects," "satisfaction with current treatment," "correct understanding of RD usage," "relief through RD," and "appropriate use of RD." On comprehensive evaluation following the second round of guidance, 81% of the patients reported overall satisfaction, and 78% reported the usefulness of guidance in pain treatment. These results suggest that positive guidance by pharmacists increases patients' satisfaction. In providing guidance, it was important to confirm the characteristics and side effects of opioids as well as the necessity of RD to patients accurately and repeatedly.

(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) and antidiabetic agent as has been previously reported. As PPARgamma agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.

[reaction: see text] An enantioselective total synthesis of (-)-adaline has been achieved starting from a chiral 6,6-disubstituted piperidone derivative previously prepared by diastereoselective allylation of a chiral tricyclic N-acyl-N,O-acetal. The key steps include lithium ion-activated SN2-type alkynylation of the tricyclic N,O-acetal leading to exclusive formation of the (6S)-ethynylpiperidine and ring-closing olefin metathesis of the (2R,6S)-cis-2,6-dialkenylpiperidine for constructing the bridged azabicyclononane.