Stereospecific alkylation of substituted adenines by the Mitsunobu coupling reaction under microwave-assisted conditions

García-Rubiño, María Eugenia; Nunez‐Carretero, M. C.; Choquesillo-Lazarte, Duane; García-Ruiz, J. M.; Madrid, Yolanda; Campos, Joaquı́n M.

doi:10.1039/c4ra01968g

Cited by 17 publications

(11 citation statements)

References 25 publications

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“…The geranyl bromide reaction also produced a minor amount of a digeranyl species ( 84 2.11). 84 This evidence further supports the proposed N-3 alkylated structures.…”

Section: Alkylation Of Purinessupporting

confidence: 76%

“…Resonance structures of an N-3 alkylated derivative of 6-(dimethylamino)purine. 84 Entries 7 -9 summarise the alkylation of 6-chloropurine (43), which resulted in the isolation of N-7 (94,96,98,99) and N-9 (95, 97, 100) alkylated regioisomers, where the latter was favoured. This is consistent with literature precedent, 62 the electronegative C-6 chlorine deactivates the pyrimidine ring to prevent alkylation at N-3.…”

Section: Scheme 211mentioning

confidence: 99%

“…This could be a result of an increase in the electron withdrawing nature of C-6. Increasing the terpenoid chain length from geranyl to farnesyl had minimal effect on activity for the adenine-( 82to The only unusual compound isolated for the purine analogues was N-6,N-9 digeranyl adenine (84). This compound exhibited the best activity in the single concentration tests (-1.4% viability), but reduced the percentage of viable HeLa cells to less than 50% at 20 μM, so further tests of 84 were not pursued since it was generally cytotoxic.…”

Section: N-9mentioning

confidence: 99%

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The Synthesis of Malonganenone Analogues for Antiparasitic Structure-Activity Relationship Analyses

Andreassend¹

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<p>The most lethal causative species of malaria, Plasmodium falciparum, has been reported as developing resistance against current antimalarial drugs in South-East Asia. New antimalarial drugs, especially those with novel modes of action, need to be established before resistance spreads. The marine natural products malonganenones A, B, and C, isolated from the gorgonian Leptogorgia gilchristi, have recently been shown to inhibit P. falciparum parasite growth. Therefore, a library of malonganenone analogues were synthesised for structure activity relationship analysis. A range of purines, purinones, and pyrimidines were alkylated with simple terpenoid chains to generate malonganenone A and B analogues, while malonganenone C analogues were made by acetylation or formylation, then methylation of terpenoid amines. The compounds were moderately active against P. falciparum infected red blood cells, but exhibited significant activity against Trypanosoma brucei, the parasite responsible for African sleeping sickness. Off target activity was assessed by assay against Escherichia coli, Staphylococcus aureus, Steptococcus uberis and HeLa cells. The overall structureactivity relationship analysis resulted in the identification of lead candidate, geranylgeranyl imidazole (146), which had IC50 values of 10.2 μM and 3.4 μM against P. falciparum and T. brucei, respectively. In addition, the minimum inhibitory concentration of 146 against S. uberis and S. aureus was 16 – 32 μM and 128 μM, respectively. Compound 146 was inactive against E. coli and was also non-toxic to HeLa cells. In addition, a geometric mixture of E and Z isomers at the alkene closest to the imidazole head group was more active than just the E isomer as for 146, which suggested the Z isomer was more active than the E isomer. Therefore, the lead compound identified within this project was the 2Z isomer of geranylgeranyl imidazole.</p>

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“…The geranyl bromide reaction also produced a minor amount of a digeranyl species ( 84 2.11). 84 This evidence further supports the proposed N-3 alkylated structures.…”

Section: Alkylation Of Purinessupporting

confidence: 76%

Section: Scheme 211mentioning

confidence: 99%

Section: N-9mentioning

confidence: 99%

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The Synthesis of Malonganenone Analogues for Antiparasitic Structure-Activity Relationship Analyses

Andreassend¹

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“…The model fitted well for both MACD and CHCD, meaning the microwave irradiation has no significant effect on the racemization ratio, which was consistent with the results of ODF design. Therefore, the results also answered the doubt that the microwave irradiation would not cause the racemization during the derivatization reaction although some racemization under microwave‐assisted conditions was reported .…”

Section: Resultsmentioning

confidence: 54%

Enantioselective analysis of bambuterol in human plasma using microwave‐assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry

Zhou

Zeng

Zhao

et al. 2017

J of Separation Science

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In this study, an enantioselective analytical method based on microwave-assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry was developed for the determination of bambuterol enantiomers in human plasma. The chiral derivatization reaction was greatly accelerated by microwave irradiation. Under the optimized conditions, both the derivatization time and separation time on column was only 3 min, and the lower limit of quantification was 2.5 pg/mL. The recoveries were in the range of 90.1-93.0% without significant matrix effect. Compared with the conventional heating chiral derivatization, microwave-assisted chiral derivatization obtained higher chiral derivatization yields with much shorter time due to the effect of microwave irradiation. Furthermore, the racemization during the derivatization reaction was systematically investigated. The results showed the concentration of acetic acid and the reaction time had significant effects on the racemization, which could be well controlled during microwave-assisted chiral derivatization for the short reaction time. Finally, this novel approach was demonstrated by determining bambuterol in human plasma of a clinical pharmacokinetic study in eight healthy volunteers. On the basis of the results, microwave-assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry as a simple and effective enantioselective analysis technique for the determination of chiral drugs in complex biological samples showed great promise.

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“…Also, adenine (9 H -purin-6-amine) was used to connect aldehyde backbone through the C–N bond from the 9-position of the purin ring. 17 Compounds 8i and 8j were synthesized using the reaction of o -phenylenediamine and 2-aminophenol and aldehyde 7f , respectively.…”

Section: Results and Discussionmentioning

confidence: 99%

Metal–Organic Framework MIL-101(Cr) as an Efficient Heterogeneous Catalyst for Clean Synthesis of Benzoazoles

et al. 2018

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A metal–organic framework [MIL-101(Cr)] was used as an efficient heterogeneous catalyst in the synthesis of benzoazoles (benzimidazole, benzothiazole, and benzoxazole), and quantitative conversion of products were obtained under optimized reaction conditions. The catalyst could be simply extracted from the reaction mixture, providing an efficient and clean synthetic methodology for the synthesis of benzoazoles. The MIL-101(Cr) catalyst could be reused without a remarkable decrease in its catalytic efficiency.

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Stereospecific alkylation of substituted adenines by the Mitsunobu coupling reaction under microwave-assisted conditions

Abstract: The Mitsunobu reaction under microwave-assisted conditions reveals a complete inversion of the stereogenic centre of the secondary alcohol giving an alkylated purine linked to a homochiral six-membered ring.

Cited by 17 publications

References 25 publications

The Synthesis of Malonganenone Analogues for Antiparasitic Structure-Activity Relationship Analyses

The Synthesis of Malonganenone Analogues for Antiparasitic Structure-Activity Relationship Analyses

Enantioselective analysis of bambuterol in human plasma using microwave‐assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry

Metal–Organic Framework MIL-101(Cr) as an Efficient Heterogeneous Catalyst for Clean Synthesis of Benzoazoles

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