Synthesis Of 1α Research Articles

Synthesis and anticancer evaluation of new lupane triterpenoid derivatives containing various substituent at the 2 or 3 position

Betulonic acid benzyl ester 1 has been subjected to a series of structural modifications for the purpose of new triterpenoid synthesis and evaluating for anticancer activity. The one-pot two step synthesis of 2α-(aminomethyl)betulinic acid benzyl ester derivatives 3a–f (yield 46–69 %) was achieved by the Mannich reaction of compound 1 with methyleneiminium salts, generated in situ from N,N-disubstituted bis(amino)methanes 2a–f by the action of acetyl chloride in dichloromethane, and subsequent reduction of aminomethylation products with sodium borohydride. Minor 2β-(aminomethyl) triterpenoids 4c,d,f were also isolated (yield 6–15 %). We found, that the stereoselective reaction of triterpenoid 1 with acetylides, generated at –78 °C from alkynes in the presence of n-BuLi, has been useful and noteworthy as the key step in providing of new alkyne substituted triterpenoids – benzyl 3-alkynyl-3-deoxy-2(3),20(29)-lupadiene-28-oates or 3-deoxy-2(3)-dehydro-28-oxoallobetulin derivative. The new compounds were examined for anticancer activity against the human cell lines (MTT assay). All tested derivatives were non-toxic on human fibroblasts. The 3‐(phenylethynyl)lupa-2(3),20(29)-diene 9 showed selective cytotoxicity on cervical cancer cell lines. Tumor cells death trigged by the most active compound 4f resulted from apoptotic processes. These data make the series of synthesized 2 or 3 substituted lupane derivatives as promising compounds with anticancer potential.

Synergistic stimulation of osteoblast differentiation of rat mesenchymal stem cells by leptin and 25(OH)D3 is mediated by inhibition of chaperone-mediated autophagy

BackgroundVitamin D is important for the mineralization of bones by stimulating osteoblast differentiation of bone marrow mesenchymal stem cells (BMMSCs). BMMSCs are a target of vitamin D action, and the metabolism of 25(OH)D3 to biologically active 1α,25(OH)2D3 in BMMSCs promotes osteoblastogenesis in an autocrine/paracrine manner. Our previous study with human BMMSCs showed that megalin is required for the 25(OH)D3-DBP complex to enter cells and for 25(OH)D3 to stimulate osteoblast differentiation in BMMSCs. Furthermore, we reported that leptin up-regulates megalin in those cells. Leptin is a known inhibitor of PI3K/AKT-dependent chaperone-mediated autophagy (CMA). In this study, we tested the hypothesis that leptin acts synergistically with 25(OH)D3 to promote osteoblastogenesis in rat BMMSCs by a mechanism that entails inhibition of PI3K/AKT-dependent CMA.MethodsBMMSCs were isolated from rat bone marrow (4-week-old male SD rats); qRT-PCR and western immunoblots or immunofluorescence were used to evaluate the expression of megalin, ALP, COL1A1, RUNX2, OSX, OSP, and CMA in rBMMSCs. The osteoblast differentiation was evaluated by ALP activity, ALP staining, and calcium deposition. The viability of rBMMSCs was assessed with the CCK-8 kit. Biosynthesis of 1α,25(OH)2D3 was measured by a Rat 1α,25(OH)2D3 ELISA Kit.ResultsThe combination of leptin and 25(OH)D3 treatment significantly enhanced osteoblast differentiation as shown by ALP activity, ALP staining, and calcium deposition, the expression of osteogenic genes ALP, COL1A1, RUNX2, OSX, and OSP by qRT-PCR and western immunoblots in rBMMSCs. Leptin enhanced the expression of megalin and synthesis of 1α,25(OH)2D3 in rBMMSCs. Our data showed that leptin inhibited CMA activity of rBMMSCs by activating PI3K/AKT signal pathway; the ability of leptin to enhance 25(OH)D3 promoted osteoblast differentiation of rBMMSCs was weakened by the PI3K/AKT signal pathway inhibitor.ConclusionsOur data reveal the mechanism by which leptin and 25(OH)D3 promote osteoblast differentiation in rBMMSCs. Leptin promoted the expression of megalin by inhibiting CMA, increased the utilization of 25(OH)D3 by rBMMSCs, and enhanced the ability of 25(OH)D3 to induce osteoblast differentiation of rBMMSCs. PI3K/AKT is at least partially involved in the regulation of CMA. These data indicate the importance of megalin in BMMSCs for vitamin D’s role in skeletal health.

Low bone mineral density due to secondary hyperparathyroidism in the GlatmTg(CAG-A4GALT) mouse model of Fabry disease.

Low bone mineral density (BMD)—diagnosed as osteoporosis or osteopenia—has been reported as a new characteristic feature of Fabry disease; however, the mechanism underlying the development of low BMD is unknown. We previously revealed that a mouse model of Fabry disease [GlatmTg(CAG‐A4GALT)] exhibits impaired functioning of medullary thick ascending limb (mTAL), leading to insufficient Ca2+ reabsorption and hypercalciuria. Here, we investigated bone metabolism in GlatmTg(CAG‐A4GALT) mice without marked glomerular or proximal tubular damage. Low BMD was detected by 20 weeks of age via micro‐X‐ray‐computed tomography. Bone histomorphometry revealed that low BMD results by accelerated bone resorption and osteomalacia. Plasma parathyroid hormone levels increased in response to low blood Ca2+—not plasma fibroblast growth factor 23 (FGF‐23) elevation—by 5 weeks of age and showed progressively increased phosphaturic action. Secondary hyperparathyroidism developed by 20 weeks of age and caused hyperphosphatemia, which increased plasma FGF‐23 levels with phosphaturic action. The expression of 1α‐hydroxylase [synthesis of 1α,25(OH)2D3] in the kidney did not decrease, but that of 24‐hydroxylase [degradation of 1α,25(OH)2D3] decreased. Vitamin D deficiency was ruled out as the cause of osteomalacia, as plasma 1α,25(OH)2D3 and 25(OH)D3 levels were maintained. Results demonstrate that secondary hyperparathyroidism due to mTAL impairment causes accelerated bone resorption and osteomalacia due to hyperphosphaturia and hypercalciuria, leading to low BMD in Fabry model mice.

Synthesis of 2α- and 2β-(3-hydroxypropyl)- 7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 and their biological activity

According to the binding mode of 14-epi-1α,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1α,25(OH)2D3 analogs were synthesized. In this paper, the synthesis and biological activity of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D3 analogs were evaluated. Interestingly, the 2β-substituted 7,8-cis-analog was a better binder for hVDR than the 2α-isomeric counterpart.

ChemInform Abstract: Design and Synthesis of 2α‐(Tetrazolylethyl)‐1α,25‐dihydroxyvitamin D3 as a High Affinity Ligand for Vitamin D Receptor

AbstractReview: 10 refs.

Synthesis of 2α- and 2β-substituted-14- epi-previtamin D 3 and their genomic activity

2α- and 2β-Substituted analogs of 14- epi-previtamin D 3 were synthesized and isolated after thermal isomerization of 14- epi-vitamin D 3 triene at 80 °C. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were tested, and the 2α-methyl-substituted analog was found to have greater genomic activity than 14- epi-previtamin D 3. We found that modification at the C2 position of the seco-steroidal skeleton afforded interesting effects for biological genomic activity for the previtamin D form as well as the natural vitamin D form.

ChemInform Abstract: Synthesis of 1α,25‐Dihydroxy‐2β‐(3‐hydroxypropoxy)vitamin D3 (Eldecalcitol) and Related Compounds by the Trost Convergent Methodology.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of C(1)–C(11) oxygen-bridged pregnanes

A general procedure for the synthesis of 1α,11α- and 1β,11α-epoxysteroids is described, using an intramolecular remote functionalization reaction involving the photolysis of 11α-hydroxysteroids in the presence of diacetoxyiodobenzene and iodine. Three 1,11-epoxypregnanes were prepared, two of them (compounds 10 and 14) are conformationally constrained analogues of steroidal hormones, compound 13 is a synthetic precursor of neurosteroids.

Design and Efficient Synthesis of 2α‐(ω‐Hydroxyalkoxy)‐1α,25‐dihydroxyvitamin D3 Analogues, Including 2‐epi‐ED‐71 and Their 20 Epimers with HL‐60 Cell Differentiation Activity.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 1α,25‐Dihydroxyvitamin D3‐26,23‐Lactams (DLAMs), a Novel Series of 1α,25‐Dihydroxyvitamin D3 Antagonist.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Characterization of five 19-nor-analogs of 1α,25(OH) 2-Vitamin D 3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties

The steroid hormone 1α,25(OH) 2-Vitamin D 3 [1α,25(OH) 2D 3] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1α,25(OH) 2D 3, can stimulate transcription of a wide variety of genes. The synthesis of 1α,25(OH) 2D 3 analogs allows the study of structure–function relationships between ligand and the VDR. 1α,25(OH) 2D 3 is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1α,25(OH) 2D 3 analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F 6-19-nor-1α,25(OH) 2D 3] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC 50 ∼10 pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.

Ultrasound assisted reductive cleavage of eudesmane and guaiane γ-enonelactones. Synthesis of 1α,7α,10α H-guaian-4,11-dien-3-one and hydrocolorenone from santonin

Ultrasound enhances the rate of reductive cleavage of the C 6–oxygen bond of sesquiterpene enonelactones. trans-Eudesmanolides 1c– 1g, cis-eudesmanolides 2a– 2c, and trans-guaianolides 4a– 4d react with Zn in acetic acid–H 2O under sonochemical conditions to afford the corresponding sesquiterpene acids 3a– 3g and 5a– 5d, respectively in good yields. Starting from 5d two natural guaianes 1α,7α,10α H-guaian-4,11-dien-3-one ( 6) and hydrocolorenone ( 7) have been prepared in good yields through a straightforward sequence.

Overview of regulatory cytochrome P450 enzymes of the vitamin D pathway

Cytochromes P450c1 and P450c24 are regulated hydroxylase enzymes that direct the bioactivation and metabolic degradation of vitamin D. The bioactivation pathway is regulated by cytochrome P450c1 through its synthesis of 1α,25(OH) 2D 3, the hormonally active form of the vitamin. Expression of the P450c1 gene is regulated at the transcription level. Promoter regions within the P450c1 gene have been identified that respond to cAMP and 1α,25(OH) 2D 3 during the respective up- and down-regulation of P450c1 gene expression. The diametric action of 1α,25(OH) 2D 3 to up-regulate P450c24 gene expression is discussed in the context of two vitamin D response elements (VDREs) that are linked functionally to an adjoining Ets-binding site. It is apparent from sequence-derived data that the P450c1 and P450c24 enzymes share only 10–25% sequence identity, yet they display functionally similar domains that are conserved across the family of cytochrome P450 enzymes. Expression of E. coli recombinant P450c1 and P450c24 enzymes, and the substrate-binding parameters for P450c24 are discussed. Finally, the natural point mutations in human P540c1 from patients with pseudovitamin D-deficiency rickets (PDDR) are discussed in the context of the enzyme’s structure and function.

Synthesis of 2α, 3α-dihydroxy-Δ4,7-6-ketosteroids, structural analogs of diaulusterols A and B

We studied various methods for synthesizing 2α,3α-dihydroxy-Δ4,7-6-ketosteroids, which are structural analogs of the ecdysteroids diaulusterols A and B.

ChemInform Abstract: New Synthetic Strategies to Vitamin D Analogues Modified at the Side Chain and D Ring. Synthesis of 1α,25‐Dihydroxy‐16‐ene‐vitamin D3 and C‐20 Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: A Short, Efficient Copper‐Mediated Synthesis of 1α,25‐Dihydroxyvitamin D2 (1α,25‐Dihydroxyergocalciferol) and C‐24 Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis of 1α,25‐Dihydroxyvitamin D3 A‐Ring Synthon by Pd‐ Catalyzed Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of 1α, 25-Dihydroxyvitamin D3 A-Ring Synthon by Pd-Catalyzed Cyclization

Synthesis of 1α, 25-Dihydroxyvitamin D₃ A-Ring Synthon by Pd-Catalyzed Cyclization

Synthesis of 1α-[19- 13C]Hydroxyvitamin D 3 and 13C NMR analysis of the conformational equilibrium of the A-ring

1α-[19- 13C]Hydroxyvitamin D 3 ( 6) was synthesized and its conformational equilibrium was investigated by means of variable temperature 13C NMR spectroscopy. The A-ring of 6 was found to exist in an equilibrium between two conformations in the ratio 52:48 at −100°C. The rate constants of the equilibrium were estimated by signal shape analysis according to the Gutowsky-Holm formulation. The thermodynamic parameters Δ G 188 K ≠ (coalescence temperature), Δ H ≠, and Δ S ≠ were deduced from the exchange rate to be 8.0 kcal/mol, 6.3 kcal/mol, and −9.0 cal/mol · deg, respectively.

Studies on steroidal plant-growth regulator: VII. Synthesis of 2α, 3α-dihydroxy-7-oxa-6-oxo-23, 24-dinor-B-homo-5α-cholanic acid and 2α, 3α-dihydroxy-7-oxa-6-oxo-24-nor-B-homo-5α-cholanic acid

Two brassinolide analogues, (2) and (3), have been synthesized from hyodeoxycholic acid (4) through a sequence of reactions as shown in Scheme 1 and 2 of the text.