25-Phosphorus analogs of vitamin D3

Dauben, William G.; Ollmann, Richard R.; Funhoff, A. S.; Leung, Suzanne S.; Norman, Anthony W.; Bishop, June E.

doi:10.1016/s0040-4039(00)92270-6

Cited by 15 publications

(4 citation statements)

References 18 publications

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“…Structural changes in both the A-ring and also the C,D-ring side chain regions have produced transcriptionally active, noncalcemic, highly antiproliferative hybrid analogues . The only side chain phosphorus-containing analogues of 1,25D 3 ever reported, phosphine oxide 2a and phosphonate 2b , showed very low antiproliferative activity . Although several side chain sulfide analogues are known, − no 16-ene side chain sulfone-containing analogues have been reported.…”

Section: Introductionmentioning

confidence: 99%

“…17 The only side chain phosphoruscontaining analogues of 1,25D 3 ever reported, phosphine oxide 2a and phosphonate 2b, showed very low antiproliferative activity. 18 Although several side chain sulfide analogues are known, [19][20][21] no 16-ene side chain sulfone-containing analogues have been reported. We describe now for the first time a series of natural A-ring 16-ene 24-and 25-sulfones, some of which are noncalcemic but potently antiproliferative and transcriptionally active even at physiologically relevant low nanomolar levels.…”

Section: Introductionmentioning

confidence: 99%

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Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃: Synthesis and Preliminary Biological Evaluation

et al. 1999

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A conceptually new series of vitamin D(3)-like nonfluorinated and fluorinated 16-ene side chain tert-butyl sulfones 3-7 has been synthesized. Even though these novel C,D-ring side chain analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) (1,1,25D(3)) lack a terminal OH group, thought previously to be essential for high biological activity, they are highly antiproliferative and, in several cases, transcriptionally active in vitro but desirably noncalcemic in vivo. The side chain sulfone group may be binding to the nVDR as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of natural 1,25D(3).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃: Synthesis and Preliminary Biological Evaluation

et al. 1999

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“…The biological activities of vitamin D derivatives possessing phosphorus atoms in the side chain were first re-ported by Dauben and col. [139]. These analogues (shown in Fig.…”

Section: Biological Studies Of Phosphonate Ana-logues Of Calcitriolmentioning

confidence: 96%

“…In such analogue, the heteroatom was introduced in the side chain by replacing C-25 as phosphine oxide moiety (9). Subsequently, this author reported the synthesis and the biological activity data of the corresponding 1 -hydroxy derivative 10, and the methyl phosphonates analogues 21 and 22 [139]. The phosphorus functionalities were introduced in that position in order to test the structural parameters involved in 25-hydroxylation and the binding to the 25hydroxyvitamin D receptor sites.…”

Section: Synthesis Of Phosphonate Analoguesmentioning

confidence: 99%

Phosphonate Analogues of 1α., 25 Dihydroxyvitamin D<sub>3</sub> are Promising Candidates for Antitumoural Therapies

Salomón¹,

Mascaró

Grioli³

et al. 2014

CTMC

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The active metabolite of vitamin D, 1α, 25 dihydroxyvitamin D3 (calcitriol) is classically known to regulate calcium and phosphate homeostasis and bone mineralization. In addition, calcitriol has also been documented to act as a potent anticancer agent in multiple cell culture and animal models of cancer. However, major side effects, such as hypercalcemia, hinder broad-spectrum therapeutic uses of calcitriol in cancer chemotherapy. Synthesis of calcitriol analogues with the same or increased antiproliferative and pro-differentiating activities, and with reduced undesired effects on calcium and bone metabolism, is getting significant attention towards rational therapeutics to treat cancer. In this regard, phosphonate analogues have been shown to display a certain degree of dissociation between the vitamin D activity in vitro and undesired hypercalcemia in vivo. However, few phosphonates have been described in the literature and fewer of them tested for antitumoral effects. Our group has synthesized a novel vitamin D analogue (EM1) bearing an alkynylphosphonate moiety that combines the low calcemic properties of phosphonates with the decreased metabolic inactivation due to the presence of a triple bond between C-23 and C-24. Biological assays demonstrated that this analogue has potent antiproliferative effects in a wide panel of tumour cell lines, even in those resistant to calcitriol treatment. Importantly, EM1 does not show toxic effects in animals, even administered at high doses and for extended periods of time. In the current review we discuss the effects and the potential application in cancer of vitamin D and its derivatives, with an emphasis on phosphonate analogues.

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Stereokontrolle in der organischen Synthese durch Verwendung der Diphenylphosphorylgruppe

Clayden

Warren

1996

Angewandte Chemie

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Im Jahr 1959 zeigte Horner, daß metallierte Alkyldiphenylphosphanoxide mit Aldehyden oder Ketonen zu Alkenen reagieren. Mit dieser Reaktion hielt die Diphenylphosphorylgruppe Einzug in die organische Synthese. Die intensive Forschung in den seither vergangenen Jahren ergab, daß diese Olefinierung ‐ die Horner‐Wittig‐Reaktion ‐ einzigartige Eigenschaften aufweist, die sie zu mehr machen als nur einfach der Phosphanoxid‐Variante der bekannteren, auf Phosphorreagentien basierenden Olefinierungen ‐ der Wittig‐Reaktion (mit Phosphoniumsalzen) und der Wadsworth‐Emmons‐Reaktion (mit Phosphonsäureestern). Der Schwerpunkt der frühen Arbeiten zur Horner‐Wittig‐Reaktion lag auf der Reaktivität der Phosphanoxide und der Regioselektivität ihrer Umsetzungen; seit kurzem ist das Potential der Ph2PO‐Gruppe, die Konfiguration von Alkenen zu kontrollieren, um das jeweils gewünschte Stereoisomer mit hoher stereochemischer Reinheit zu erhalten, in den Vordergrund getreten. Aus den Untersuchungen dieser stereo‐kontrollierten Horner‐Wittig‐Reaktionen wuchs die Erkenntnis, daß mit der Ph2PO‐Gruppe nicht nur die zweidimensionale Konfiguration von Alkenen kontrolliert werden kann, sondern ganz allgemein dreidimensionale. Nach einer kurzen Einführung in die Chemie der Phosphanoxide werden wir uns hier mit der Horner‐Wittig‐Reaktion sowohl in ihrer ursprünglichen Form als auch mit “stereokontrollierenden” Varianten befassen. Anschließend werden wir über den stereoselektiven Aufbau von Molekülen berichten, die eine Ph2PO‐Gruppe enthalten, wobei die Schwerpunkte auf dem Einfluß der Ph2PO‐Gruppe auf den stereochemischen Verlauf der Reaktion sowie auf der Rolle der einzigartigen Kombination ihrer Eigenschaften ‐ sterischer Anspruch, Elektronegativität und Lewis‐Basizität ‐ bei der Kontrolle dieser Reaktionen liegen werden. Schließlich werden wir einen praktischen Ratgeber zu dieser Chemie präsentieren, in dem alle Arten von funktionalisierten Alkenen behandelt werden, die mit Hilfe der Ph2PO‐Gruppe hergestellt wurden, und allgemeine Richtlinien enthalten sind, die, wie wir hoffen, dem präparativ arbeitenden Chemiker helfen werden, das beste aus dem zu machen, was die Ph2PO‐Gruppe zu bieten hat.

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25-Phosphorus analogs of vitamin D3

Cited by 15 publications

References 18 publications

Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃: Synthesis and Preliminary Biological Evaluation

Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃: Synthesis and Preliminary Biological Evaluation

Phosphonate Analogues of 1α., 25 Dihydroxyvitamin D<sub>3</sub> are Promising Candidates for Antitumoural Therapies

Stereokontrolle in der organischen Synthese durch Verwendung der Diphenylphosphorylgruppe

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25-Phosphorus analogs of vitamin D3

Cited by 15 publications

References 18 publications

Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D3: Synthesis and Preliminary Biological Evaluation

Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D3: Synthesis and Preliminary Biological Evaluation

Phosphonate Analogues of 1&#945;., 25 Dihydroxyvitamin D<sub>3</sub> are Promising Candidates for Antitumoural Therapies

Stereokontrolle in der organischen Synthese durch Verwendung der Diphenylphosphorylgruppe

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Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃: Synthesis and Preliminary Biological Evaluation

Conceptually New Sulfone Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃: Synthesis and Preliminary Biological Evaluation

Phosphonate Analogues of 1α., 25 Dihydroxyvitamin D<sub>3</sub> are Promising Candidates for Antitumoural Therapies