A De Novo Approach to the Synthesis of Glycosylated Methymycin Analogues with Structural and Stereochemical Diversity

Borisova, Svetlana A.; Guppi, Sanjeeva R.; Kim, Hak Joong; Wu, Bulan; Penn, John H.; Liu, Hung Wen; O’Doherty, George A.

doi:10.1021/ol102144g

Cited by 36 publications

(23 citation statements)

References 43 publications

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“…Previously, we reported both a traditional carbohydrate 11 and a de novo asymmetric approach 12–13 to SL0101 ( 1 ) 14 and several carbohydrate analogues ( 1,1a-d , Scheme 1). 15 While the carbohydrate approach has some real advantages in terms of convergency, the de novo approach has the advantage of being amenable to the divergent late stage substitution of the pyranone ring.…”

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confidence: 99%

Improving the Affinity of SL0101 for RSK Using Structure-Based Design

Mrozowski

Vemula

et al. 2013

ACS Med. Chem. Lett.

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Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product, SL0101 (kaempferol 3-O-(3″,4″-di-O-acetyl-α-L-rhamnopyranoside), has been shown to be a RSK selective inhibitor. However, the Ki for SL0101 is 1 μM with a half-life of less than 30 min in vivo. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5″-n-propyl group on the rhamnose that has > 40-fold improved affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5″-n-propyl analogue to inhibit MCF-7 proliferation was only two-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5″-n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.

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confidence: 99%

Improving the Affinity of SL0101 for RSK Using Structure-Based Design

Mrozowski

Vemula

et al. 2013

ACS Med. Chem. Lett.

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“…Compounds 1–9 were synthesized as described in Ref. . NMR assignment strategy, typical parameters for the applied 1D and 2D NMR experiments, and procedure of determination of coupling constants ( J HH ) using iterative simulation program (gNMR) are given as supplementary material.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we have reported a new approach for the synthesis of stereochemically diverse (L/D and α / β ) glycosylated 8,9‐dihydro‐10‐deoxymethymycin analogs 3–9 . As part of our synthetic study, we now report the detailed analysis of the 1 H and 13 C NMR spectra of 1–9 and also a conformational NMR study of two methymycin aglycones 1 and 2 along with the use of molecular modeling methods.…”

Section: Introductionmentioning

confidence: 99%

A conformational NMR analysis of methymycin aglycones: complete and unambiguous assignments of stereochemically diverse glycosylated methymycin analogs by 1D and 2D NMR techniques and molecular modeling

Akhmedov

Gannett

et al. 2013

Magnetic Reson in Chemistry

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The (1)H and (13)C NMR spectra of 10-deoxymethynolide (1), 8.9-dihydro-10-deoxymethynolide (2) and its glycosylated derivatives (3-9) were analyzed using gradient-selected NMR techniques, including 1D TOCSY, gCOSY, 1D NOESY (DPFGSENOE), NOESY, gHMBC, gHSQC and gHSQC-TOCSY. The NMR spectral parameters (chemical shifts and coupling constants) of 1-9 were determined by iterative analysis. For the first time, complete and unambiguous assignment of the (1)H NMR spectrum of 10-deoxymethynolide (1) has been achieved in CDCl(3), CD(3)OD and C(6)D(6) solvents. The (1)H NMR spectrum of 8,9-dihydro-10-deoxymethynolide (2) was recorded in CDCl(3), (CD(3))(2)CO and CD(3)OD solutions to determine the conformation. NMR-based conformational analysis of 1 and 2 in conjugation with molecular modeling concluded that the 12-membered ring of the macrolactones may predominantly exist in a single stable conformation in all solvents examined. In all cases, a change in solvent caused only small changes in chemical shifts and coupling constants, suggesting that all glycosylated methymycin analogs exist with similar conformations of the aglycone ring in solution.

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“…302 Mezzettiaside-2 ( 271 ) and congeners were synthesized as anticancer/antibiotic oligosaccharides. 88 Merremoside D 272 299 and carbohydrates including digitoxin ( 273 , anticancer properties), 303 vineomycinone B2 ( 274 ), 304 vineomycin B2 trisaccharide ( 276 ) 305 (antitumor and antibacterial activities), methymycin analogues such as 275 (antibiotic activity), 306 and landomycins A and E ( 277a,b , antitumor activity) 307 were also synthesized using these protocols.…”

Section: Introductionmentioning

confidence: 99%

Achmatowicz reaction and its application in the syntheses of bioactive molecules

Ghosh

Brindisi

2016

RSC Adv.

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Substituted pyranones and tetrahydropyrans are structural subunits of many bioactive natural products. Considerable efforts are devoted toward the chemical synthesis of these natural products due to their therapeutic potential as well as low natural abundance. These embedded pyranones and tetrahydropyran structural motifs have been the subject of synthetic interest over the years. While there are methods available for the syntheses of these subunits, there are issues related to regio and stereochemical outcomes, as well as versatility and compatibility of reaction conditions and functional group tolerance. The Achmatowicz reaction, an oxidative ring enlargement of furyl alcohol, was developed in the 1970s. The reaction provides a unique entry to a variety of pyranone derivatives from functionalized furanyl alcohols. These pyranones provide convenient access to substituted tetrahydropyran derivatives. This review outlines general approaches to the synthesis of tetrahydropyrans, covering general mechanistic aspects of the Achmatowicz reaction or rearrangement with an overview of the reagents utilized for the Achmatowicz reaction. The review then focuses on the synthesis of functionalized tetrahydropyrans and pyranones and their applications in the synthesis of natural products and medicinal agents.

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A De Novo Approach to the Synthesis of Glycosylated Methymycin Analogues with Structural and Stereochemical Diversity

Cited by 36 publications

References 43 publications

Improving the Affinity of SL0101 for RSK Using Structure-Based Design

Improving the Affinity of SL0101 for RSK Using Structure-Based Design

A conformational NMR analysis of methymycin aglycones: complete and unambiguous assignments of stereochemically diverse glycosylated methymycin analogs by 1D and 2D NMR techniques and molecular modeling

Achmatowicz reaction and its application in the syntheses of bioactive molecules

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