Gary H. Posner

Name:

Organization: Johns Hopkins University

Department: Department of Chemistry

Title:

Chemicals
References

Highly regiocontrolled and stereocontrolled syntheses of polysubstituted aminocyclohexanes: mild inverse-electron-demand Diels–Alder cycloadditions of electrophilic 2-pyridones

Co-reporter:Ryan C. Conyers, Jennifer R. Mazzone, Maxime A. Siegler, Gary H. Posner

Tetrahedron Letters 2016 Volume 57(Issue 30) pp:3344-3348

Publication Date(Web):27 July 2016

DOI:10.1016/j.tetlet.2016.06.068

•Developed procedure for IEDDA cycloadditions under mild conditions and avoiding undesired N- to O-sulfonyl group migration.•These [4+2] cycloadditions very strongly favor regioselective and stereoselective formation of endo bicyclic lactams.•These IEDDA cycloadditions produce highly functionalized pentasubstituted and hexasubstituted cyclohexanes.Strongly electrophilic N-arenesulfonyl-2-pyridone-3-carboxylate methyl esters complex with zinc dibromide and then react with nucleophilic benzyl vinyl ether or benzyloxyallene to achieve inverse-electron-demand Diels–Alder (IEDDA) cycloadditions. These cycloadducts are produced on gram scale and in 77–89% yields, importantly without the use of high pressure. These 4+2 cycloadditions strongly favor regioselective and stereoselective formation of endo bicyclic lactams as established by X-ray crystallography. These bicyclic lactams undergo useful reactions, including reductive cleavage of the N-sulfonyl group, exo-syn-dihydroxylations, and lactam ring-opening to produce a variety of aminocyclitols.

Antimalarial chemotherapy: Orally curative artemisinin-derived trioxane dimer esters

Co-reporter:Ryan C. Conyers, Jennifer R. Mazzone, Abhai K. Tripathi, David J. Sullivan, Gary H. Posner

Bioorganic & Medicinal Chemistry Letters 2015 Volume 25(Issue 2) pp:245-248

Publication Date(Web):15 January 2015

DOI:10.1016/j.bmcl.2014.11.064

Eight new artemisinin-derived trioxane dimer esters 5 have been prepared and tested for antimalarial efficacy in malaria-infected mice. At a single oral dose of only 6 mg/kg combined with 18 mg/kg of mefloquine, each of the dimer esters 5 outperformed the antimalarial drug artemether (2). The most efficacious dimer, dichlorobenzoate ester 5h, prolonged mouse survival past day 30 of infection with three of the four mice in this group having no detectable parasitemia and appearing and acting healthy on day 30.Single oral dose partial cure of malaria-infected mice.

The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether

Co-reporter:Ryan C. Conyers, Jennifer R. Mazzone, Maxime A. Siegler, Abhai K. Tripathi, David J. Sullivan, Bryan T. Mott, Gary H. Posner

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 5) pp:1285-1289

Publication Date(Web):1 March 2014

DOI:10.1016/j.bmcl.2014.01.059

Sixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5 mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25–27 days) of malaria-infected mice.

Antimalarial chemotherapy: Artemisinin-derived dimer carbonates and thiocarbonates

Co-reporter:Jennifer R. Mazzone, Ryan C. Conyers, Abhai K. Tripathi, David J. Sullivan, Gary H. Posner

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 11) pp:2440-2443

Publication Date(Web):1 June 2014

DOI:10.1016/j.bmcl.2014.04.025

Several 2-carbon-linked trioxane dimer secondary alcohol carbonates 14 and thiocarbonates 15, combined with mefloquine and administered in a low single oral dose, prolonged the survival times of malaria-infected mice much more effectively than the popular monomeric antimalarial drug artemether plus mefloquine. Three dimer carbonates 14 and one dimer thiocarbonate 15 partially cured malaria-infected mice.

Artemisinin-derived dimer phosphate esters as potent anti-cytomegalovirus (anti-CMV) and anti-cancer agents: A structure–activity study

Co-reporter:Bryan T. Mott, Ran He, Xiaochun Chen, Jennifer M. Fox, Curt I. Civin, Ravit Arav-Boger, Gary H. Posner

Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 13) pp:3702-3707

Publication Date(Web):1 July 2013

DOI:10.1016/j.bmc.2013.04.027

We recently reported the anti-cancer and anti-cytomegalovirus (CMV) activity of artemisinin-derived trioxane diphenylphosphate dimer 838. To probe the relationship between chemical structure and anti-CMV and anti-cancer activities, we now report synthesis and evaluation of a series of eight new dimer phosphate ester analogs of 838. This series of novel molecules was screened against human foreskin fibroblasts (HFFs) infected with CMV and against the human Jurkat T cell acute lymphoblastic leukemia cell line. This SAR study confirms the very high anti-CMV and anti-cancer potencies of dimer diphenyl phosphate ester 838 without its being toxic to normal cells.

Highly stereocontrolled and regiocontrolled syntheses of polyoxygenated [2.2.2]oxabicyclic synthons

Co-reporter:Rachel D. Slack, Maxime A. Siegler, Gary H. Posner

Tetrahedron Letters 2013 Volume 54(Issue 46) pp:6267-6270

Publication Date(Web):13 November 2013

DOI:10.1016/j.tetlet.2013.09.030

Highly oxygenated cyclohexanes (known as cyclitols or carba-sugars) were synthesized regiospecifically and stereoselectively via a key inverse electron demand Diels–Alder cycloaddition of electron poor 2-pyrones with electron rich tert-butyldimethylsilyl vinyl ether. The resulting [2.2.2]oxabicyclic lactones proved to be versatile synthons; syn-dihydroxylations were achieved with very high stereocontrol, with up to five stereocenters being produced from commercially available or easily prepared planar starting materials.Figure optionsDownload full-size imageDownload as PowerPoint slide

Malaria-Infected Mice Are Completely Cured by One 6 mg/kg Oral Dose of a New Monomeric Trioxane Sulfide Combined with Mefloquine

Co-reporter:Rachel D. Slack ; Bryan T. Mott ; Lauren E. Woodard ; Abhai Tripathi ; David Sullivan ; Elizabeth Nenortas ; Sonya C. T. Girdwood ; Theresa A. Shapiro

Journal of Medicinal Chemistry 2012 Volume 55(Issue 1) pp:291-296

Publication Date(Web):November 30, 2011

DOI:10.1021/jm201214d

Sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in Plasmodium berghei infected mice. Of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-arteSanilide 12d was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally.

Malaria-Infected Mice Live Until at Least Day 30 after a New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together in a Single, Low, Oral Dose

Co-reporter:Alexander M. Jacobine ; Jennifer R. Mazzone ; Rachel D. Slack ; Abhai K. Tripathi ; David J. Sullivan

Journal of Medicinal Chemistry 2012 Volume 55(Issue 17) pp:7892-7899

Publication Date(Web):August 14, 2012

DOI:10.1021/jm3009986

In only three steps and in 21–67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection, and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days).

Antimalarial peroxides: advances in drug discovery and design

Co-reporter:Rachel D. Slack, Alexander M. Jacobine and Gary H. Posner

MedChemComm 2012 vol. 3(Issue 3) pp:281-297

Publication Date(Web):07 Dec 2011

DOI:10.1039/C2MD00277A

Cyclic peroxides such as the plant-derived 1,2,4-trioxane artemisinin and its derivatives are short-lived, rapidly-acting antimalarials that are now usually combined with standard long-lived, alkaloidal antimalarials; such artemisinin combination therapy (ACT) is the worldwide standard operating procedure for malaria chemotherapy. This review discusses antimalarial monomeric and dimeric derivatives of artemisinin, peroxides not derived from artemisinin, and finally hybrids containing one peroxide unit covalently linked to a non-peroxide unit. Emphasis is placed on the antimalarial effectiveness of these diverse cyclic peroxides and on the simplicity of their synthesis.

A single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice

Co-reporter:Deuk Kyu Moon, Abhai Tripathi, David Sullivan, Maxime A. Siegler, Sean Parkin, Gary H. Posner

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 9) pp:2773-2775

Publication Date(Web):1 May 2011

DOI:10.1016/j.bmcl.2010.09.123

Four 5-carbon-linked trioxane dimer orthoesters (6a–6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.

Asymmetric, Organocatalytic, Three-Step Synthesis of α-Hydroxy-(E)-β,γ-unsaturated Esters

Co-reporter:Lindsey C. Hess and Gary H. Posner

Organic Letters 2010 Volume 12(Issue 9) pp:2120-2122

Publication Date(Web):April 8, 2010

DOI:10.1021/ol100615j

An efficient and enantiocontrolled three-step synthesis of α-hydroxy-(E)-β,γ-unsaturated esters is reported. Enantioenriched α-selenyl aldehydes, prepared in one step by asymmetric, organocatalytic α-selenylation of aldehydes, were directly subjected to a Wittig reaction followed by allylic selenide to selenoxide oxidation and final spontaneous [2,3]-sigmatropic rearrangement to yield the target compounds in 43−65% overall yield and in 94−97% ee.

α-Chloro-β,γ-ethylenic Esters: Enantiocontrolled Synthesis and Substitutions

Co-reporter:Douglas T. Genna, Christopher P. Hencken, Maxime A. Siegler, and Gary H. Posner

Organic Letters 2010 Volume 12(Issue 20) pp:4694-4697

Publication Date(Web):September 20, 2010

DOI:10.1021/ol102142a

Chiral nonracemic γ-seleno-α,β-ethylenic esters, when treated with sulfuryl chloride and ethyl vinyl ether in hexanes, produced α-chloro-β,γ-ethylenic esters in 65−75% yields, with ee values of 95−97%, and with 1,3-syn transfer of chirality. Reaction of these allylic chloride electrophiles with methylcuprate and with sodium azide nucleophiles afforded exclusively γ-substituted-α,β-ethylenic esters with faithful anti-transfer of chirality on multigram scale.

Malaria-Infected Mice Are Cured by a Single Oral Dose of New Dimeric Trioxane Sulfones Which Are Also Selectively and Powerfully Cytotoxic to Cancer Cells

Co-reporter:Andrew S. Rosenthal ; Xiaochun Chen ; Jun O. Liu ; Diana C. West ; Paul J. Hergenrother ; Theresa A. Shapiro

Journal of Medicinal Chemistry 2009 Volume 52(Issue 4) pp:1198-1203

Publication Date(Web):February 2, 2009

DOI:10.1021/jm801484v

A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines.

Malaria-Infected Mice Live until at Least Day 30 after a New Monomeric Trioxane Combined with Mefloquine Are Administered Together in a Single Low Oral Dose†

Co-reporter:Lauren E. Woodard ; Wonsuk Chang ; Xiaochun Chen ; Jun O. Liu ; Theresa A. Shapiro

Journal of Medicinal Chemistry 2009 Volume 52(Issue 23) pp:7458-7462

Publication Date(Web):July 8, 2009

DOI:10.1021/jm9005934

In only five simple steps and 48% overall yield from the natural trioxane artemisinin, the thermally and hydrolytically stable trioxane fluoroanilide 4b has been prepared. Upon one oral dose of only 6.8 mg/kg of monomeric trioxane 4b combined with 20 mg/kg of mefloquine hydrochloride, all of the malaria-infected mice lived until at least day 30 post infection. Of the five mice in this surviving group, four (80%) were completely cured (no parasites in their blood) and one mouse had 4% blood parasitemia. Importantly, the efficacy of this ACT chemotherapy using monomeric trioxane 4b plus mefloquine hydrochloride is considerably better than the efficacy under the same conditions using the popular trioxane drug artemether plus mefloquine hydrochloride.

‘Novel alkyl side chain sulfone 1α,25-dihydroxyvitamin D3 analogs: A comparison of in vitro antiproliferative activities and in vivo calcemic activities’

Co-reporter:Aimee R. Usera, Patrick Dolan, Thomas W. Kensler, Gary H. Posner

Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 15) pp:5627-5631

Publication Date(Web):1 August 2009

DOI:10.1016/j.bmc.2009.06.033

The replacement of a t-butyl group with a trifluoromethyl group has profound effects on the biological profile of 1α,25-dihydroxyvitamin D3 sulfone analogs. Investigation of whether the improved biological activities are due to steric and electronic factors of the trifluoromethyl group led to the design, synthesis and biological evaluation of two analogous alkyl sulfone molecules, methyl sulfone (AU-16-ene-25-SO2–CH3) and isopropyl sulfone (AU-16-ene-25-SO2–i-Pr). These alkyl sulfones are sterically comparable to, but electronically very different from a trifluoromethyl group. The syntheses, antiproliferative activities and calcemic activities of these new alkyl sulfones are presented herein. In comparing the in vitro antiproliferative profiles of the new alkyl sulfone 1α,25-dihydroxyvitamin D3 analogs with the trifluoromethylsulfone and an analogous t-butyl sulfone, the activities increase in the following order: CH3

New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3

Co-reporter:Heung Bae Jeon, Gary H. Posner

Tetrahedron 2009 65(7) pp: 1235-1240

Publication Date(Web):

DOI:10.1016/j.tet.2008.12.034

Malaria-Infected Mice Are Cured by Oral Administration of New Artemisinin Derivatives

Co-reporter:Gary H. Posner ; Wonsuk Chang ; Lindsey Hess ; Lauren Woodard ; Sandra Sinishtaj ; Aimee R. Usera ; William Maio ; Andrew S. Rosenthal ; Alvin S. Kalinda ; John G. D’Angelo ; Kimberly S. Petersen ; Remo Stohler ; Jacques Chollet ; Josefina Santo-Tomas ; Christopher Snyder ; Matthias Rottmann ; Sergio Wittlin ; Reto Brun ;Theresa A. Shapiro

Journal of Medicinal Chemistry 2008 Volume 51(Issue 4) pp:1035-1042

Publication Date(Web):January 31, 2008

DOI:10.1021/jm701168h

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 × 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6–7 postinfection. At only 3 × 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14–17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7–13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.

Antimalarial sulfide trioxanes: a revision of mechanism

Co-reporter:Gary H. Posner;Wonsuk Chang

Journal of Physical Organic Chemistry 2008 Volume 21( Issue 7-8) pp:538-540

Publication Date(Web):

DOI:10.1002/poc.1307

Abstract

The mechanism by which an antimalarially inactive sulfanyl trioxane reacts with ferrous iron is revised. Although originally proposed to involve a short-lived high-valent iron-oxo intermediate, the revised mechanism involves FeBr₂ acting as a weak Lewis acid promoting intramolecular redox chemistry between the peroxide unit and the resident sulfanyl sulfur atom; one of the peroxide oxygen atoms is transferred intramolecularly to the neighboring sulfide sulfur atom, oxidizing it into a sulfoxide and reducing the trioxane into a non-peroxidic dioxolane. This facile ferrous iron-triggered conversion of the parent 1,2,4-trioxane sulfide into the corresponding 1,3-dioxolane sulfoxide accounts for the observed lack of antimalarial activity of the parent sulfanyl trioxane without invoking the intermediacy of a high-valent iron-oxo species. Copyright © 2008 John Wiley & Sons, Ltd.

Antiproliferative, low-calcemic, fluorinated sulfone analogs of 1α,25-dihydroxyvitamin D3: Chemical synthesis and biological evaluation

Co-reporter:Aimee R. Usera, Patrick M. Dolan, Thomas W. Kensler, Gary H. Posner

Bioorganic & Medicinal Chemistry 2007 Volume 15(Issue 16) pp:5509-5518

Publication Date(Web):15 August 2007

DOI:10.1016/j.bmc.2007.05.051

Novel fluorinated sulfone analogs of the hormone 1α,25-dihydroxyvitamin D3 have been designed and synthesized in order to study the biological effects of fluorine incorporation at the terminus of the C,D-ring side chain. Although biologically active 26,27-hexafluorinated 1α,25-dihydroxyvitamin D3 analogs have been synthesized previously, this investigation reports the first successful fluorinated series in which trifluoromethyl sulfone analogs present a favorable biological profile. This study shows that two new analogs featuring incorporation of a synthetically simple single trifluoromethyl sulfone group have significantly increased antiproliferative activity while causing desirably low in vivo calciuria relative to that of calcitriol. Incorporation of additional fluorines, as in a perfluorobutyl analog, results in a loss of antiproliferative activity.

Novel A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation

Co-reporter:Gary H. Posner, S.H. Tony Lee, Hyung Jin Kim, Sara Peleg, Patrick Dolan, Thomas W. Kensler

Bioorganic & Medicinal Chemistry 2005 Volume 13(Issue 8) pp:2959-2966

Publication Date(Web):15 April 2005

DOI:10.1016/j.bmc.2005.02.005

Prepared from a commercial prostaglandin building block, novel vitamin D3 analogs with a contracted five-membered A-ring were designed and synthesized to mimic the A-ring diol structure of the natural hormone 1α,25-dihydroxyvitamin D3. Prepared from commercial 1,4-cyclohexanedione, a structurally simplified analog was designed and synthesized in which a suitably oriented primary allylic hydroxyl group at the C-2 position might be a surrogate for the biologically important 1α-OH in the natural hormone.

A-ring hydroxymethyl 19-nor analogs of the natural hormone 1α,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation

Co-reporter:Mark A. Hatcher, Sara Peleg, Patrick Dolan, Thomas W. Kensler, Amy Sarjeant, Gary H. Posner

Bioorganic & Medicinal Chemistry 2005 Volume 13(Issue 12) pp:3964-3976

Publication Date(Web):2 June 2005

DOI:10.1016/j.bmc.2005.04.010

A series 5–8 of 1- and 3-CH2OH 19-nor analogs of the hormone calcitriol (1) has been prepared. Surprisingly, 19-nor 1α-CH2OH analog 5a is more antiproliferative at 100 nM concentration than the corresponding regioisomeric analog 6a with the natural 1α-OH group, and 1α-CH2OH hybrid analog 7a is similar in antiproliferative potency to calcitriol (1) even at low nanomolar concentrations.

Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1α,25-dihydroxyvitamin D3

Co-reporter:Gary H. Posner, Hyung Jin Kim, Mehmet Kahraman, Heung Bae Jeon, Byung Chul Suh, Hongbin Li, Patrick Dolan, Thomas W. Kensler

Bioorganic & Medicinal Chemistry 2005 Volume 13(Issue 19) pp:5569-5580

Publication Date(Web):1 October 2005

DOI:10.1016/j.bmc.2005.06.031

A series 2a–4b of seven new side-chain ketone analogs of calcitriol (1) have been prepared. Unexpectedly, several of these 24- and 25-tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (1) in vivo. In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a.

Enantiomeric 1,2,4-Trioxanes Display Equivalent in vitro Antimalarial Activity Versus Plasmodium falciparum Malaria Parasites: Implications for the Molecular Mechanism of Action of the Artemisinins

Co-reporter:Paul M. O’Neill Dr.;Sarah L. Rawe Dr.;Kristina Borstnik;Alison Miller;Stephen A. Ward ;Patrick G. Bray Dr.;Jill Davies;Chang Ho Oh

ChemBioChem 2005 Volume 6(Issue 11) pp:

Publication Date(Web):13 OCT 2005

DOI:10.1002/cbic.200500048

The aim of this study was to synthesise pure enantiomers of potent antimalarial 1,2,4-trioxanes, which are related to the natural antimalarial artemisinin, and then to assay each against a panel of Plasmodium falciparum strains. The working hypothesis was that if the artemisinin derivatives interact with a specific protein-target site, then there should be stereoselective differences in their activity. In five different P. falciparum isolates, however, the trioxane enantiomers (+)-7 a, (−)-7 a and (+)-7 b, (−)-7 b, showed the same level of in vitro antiparasitic activity.

Organic Chemistry of Vitamin D Analogues (Deltanoids)

Co-reporter:Gary H. Posner;Mehmet Kahraman

European Journal of Organic Chemistry 2003 Volume 2003(Issue 20) pp:

Publication Date(Web):8 SEP 2003

DOI:10.1002/ejoc.200300264

An increasing number of synthetic vitamin D analogues (deltanoids) are now being used as sensitive molecular biology probes and also as new drug candidates and new drugs for treatment of various human diseases. The design and stereocontrolled synthesis of such new deltanoids are guided by considering catabolism inhibition and by using large steroidal chirons and small steroid-derived chirons. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Organic Chemistry of Vitamin D Analogues (Deltanoids)

Co-reporter:Gary H. Posner;Mehmet Kahraman

European Journal of Organic Chemistry 2003 Volume 2003(Issue 24) pp:

Publication Date(Web):4 DEC 2003

DOI:10.1002/ejoc.200300729

A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin

Co-reporter:Gary H. Posner, Kenneth R. Crawford, Sara Peleg, Jo-Ellen Welsh, Saara Romu, David A. Gewirtz, Mona S. Gupta, Patrick Dolan, Thomas W. Kensler

Bioorganic & Medicinal Chemistry 2001 Volume 9(Issue 9) pp:2365-2371

Publication Date(Web):September 2001

DOI:10.1016/S0968-0896(01)00159-6

Novel side-chain diene sulfones 5, analogues of the natural hormone 1α,25-dihydroxyvitamin D3 (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Company's drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9→10) and Horner–Wadsworth–Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1α,3β-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 μg/kg of rat body weight.Graphic

Difluoromethyl analogs of the natural hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation

Co-reporter:Gary H. Posner, Byung Chul Suh, Kimberly S. Petersen, Patrick Dolan, Elin S. Agoston, Thomas W. Kensler, John T. Koh, Sara Peleg

The Journal of Steroid Biochemistry and Molecular Biology (March 2007) Volume 103(Issues 3–5) pp:213-221

Publication Date(Web):1 March 2007

DOI:10.1016/j.jsbmb.2006.12.024

Three new Vitamin D analogs 3–5 incorporating a –CHF2 group as an –OH surrogate have been prepared. Two of these new analogs (3 and 5) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the natural hormone calcitriol. The transcriptional activity of the 25-CHF2 analog 3 is higher than that of the 1-CHF2 analog 4.