Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

Krajčovičová, Soňa; Soural, Miroslav

doi:10.1021/acscombsci.6b00061

Cited by 10 publications

(5 citation statements)

References 68 publications

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“…We synthesized new 2,6,9-trisubstituted purines 4a-k (Series I), 4l-u (Series II), and 7a-j (Series III), using short, simple, and efficient synthetic methods as described in Schemes 1 and 2 [22,34,35]. We obtained 21 compounds of Series I and II in three steps using 2-fluoro-6-chloropurine (1) as a starting material.…”

Section: Synthesismentioning

confidence: 99%

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Salas

Zárate

Kryštof

et al. 2019

IJMS

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We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

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Section: Synthesismentioning

confidence: 99%

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Salas

Zárate

Kryštof

et al. 2019

IJMS

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“…That is the reason why some purine analogues have been approved for their clinical application as chemotherapeutic agents (antiviral, antiprotozoal, antifungal, and anticancer agents) and pharmacodynamic drugs (coronary vasodilator) [11,12]. Therefore, considering the pharmacological properties elicited by purine derivatives, these types of heterocyclic compounds have attracted the interest of the synthetic and medicinal chemists to preparing various substituted analogues, which can be drug candidates with enhanced pharmacological activities and significant physicochemical properties [9,13,14].…”

Section: Introductionmentioning

confidence: 99%

“…According to the aforementioned, in the last decades, several synthetic procedures to obtain di‐ or trisubstituted purines have been reported, where the positions C‐2, C‐6, and N‐9 are the most explored. The influences of different substituents in these positions in several bioactive purine derivatives have been extensively studied, and according to these results, optimal substituents have been identified [6,7,14–16]. An alkylated side chain at C‐2 position certainly opens the path to a significant range of possible modifications of the parent purines.…”

Section: Introductionmentioning

confidence: 99%

Convergent synthesis, drug target prediction, and docking studies of new 2,6,9‐trisubstituted purine derivatives

Villegas

Satheeshkumar

Ballesteros-Casallas

et al. 2021

Journal of Heterocyclic Chem

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A set of new 2,6,9‐trisubstituted purine derivatives were designed and synthesized from 6‐chloro‐2‐fluoro‐9‐alkyl‐9H‐purine as the key starting material. These purines were synthesized via a multistep protocol and finally subjected to SNAr with various aminopiperidinyl salts. The structures of these compounds were established by substantiating them through spectral techniques like FT‐IR, 1H‐NMR, 13C‐NMR, and 19F‐NMR. In addition, for two purine derivatives, a reverse screening strategy based on ligand similarity (PharmMapper web server) resulted in a set of predicted protein target candidates. Interestingly, for both purines, the main potential target candidates belonged to key proteins involved within signaling pathways that are related to proliferation or survival of cancer cells. These proteins correspond mainly to enzymes and specifically kinases. To check if our purines could be ligands for two kinases involved in cancer, docking studies were performed. The results indicated that these purines fitted in the same cavity of crystalized inhibitors. Therefore, in this work we are developed new purine derivatives that could be good inhibitors of some kinases.

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“…In view of the importance of modified purines in drug discovery and functional nucleic acids, various syntheses of substituted purines are reported in the literature that attend to multiple ring substitution reactions (at C‐2, ‐6, ‐8, and N‐9). While de‐novo synthesis of substituted purines starting from imidazole or pyrimidine derivatives have been explored [19], modular synthesis on halo‐purine templates, either by S R N reaction with heteroatomic (N, S, O) nucleophiles or via Pd/Ni‐catalyzed couplings to introduce carbon‐ and heteroatom‐based substitutents [20], with options for solid phase extensions [21], has obviously gained more traction. Diazonium chemistry has played a crucial role toward these ends in providing streamlined access to various halo‐purines via diazotization/Sandmeyer reactions of adenine, guanine, and their nucleosides.…”

Section: Introductionmentioning

confidence: 99%

Application of diazonium chemistry in purine modifications: A focused review

Sengupta

Das

2021

Journal of Heterocyclic Chem

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Deaminative modifications of purines via diazonium chemistry have long been the cornerstone in modified nucleoside synthesis. The purpose of this review is to bring into focus the impact of dediazoniative methods such as non‐aqueous Sandmeyer halogenations, fluorination, arylation, and carbon‐heteroatom bond formations on natural purines and their nucleosides as versatile tools for purine modifications en route to various nucleoside drugs, drug discovery scaffolds, and adducted oligonucleotides of biomedical interests. Metal free reactions of arenediazonium salts with purine nucleosides for the synthesis of 8‐aryl purines, in particular, 8‐aryl guanosines and photochromic 8‐arylazo purines are also highlighted. The treatise is expected to create broad interest among organic and biological chemists for further explorations in this area.

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Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

Abstract: This Review summarizes all of the currently described strategies applicable for the solid-phase synthesis of purine derivatives. The individual approaches are classified according to the immobilization procedure used resulting in a linkage of the final scaffold at various positions.

Cited by 10 publications

References 68 publications

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Convergent synthesis, drug target prediction, and docking studies of new 2,6,9‐trisubstituted purine derivatives

Application of diazonium chemistry in purine modifications: A focused review

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