İlaç tasarımında çok yönlü iskelet yapılar olarak kalkonlar: sentez, yapı-aktivite ilişkisi (SAR) ve antikanser potansiyeli

Öz

Kalkonlar, yapısal olarak basit ancak yüksek derecede çok yönlü α,β-doymamış karbonil bileşikleri sınıfını temsil etmekte olup, antikanser ilaç keşfi alanında önemli ölçüde ilgi görmektedir. Modüler yapıları, özellikle Claisen–Schmidt kondenzasyonu başta olmak üzere iyi tanımlanmış sentez yöntemleri aracılığıyla etkin bir yapısal çeşitlendirmeye olanak tanımaktadır. Her iki aromatik halka üzerindeki sübstitüentlerin sistematik olarak değiştirilmesi, elektronik özelliklerin, moleküler planarlığın ve fizikokimyasal karakteristiklerin ince ayarlanmasını mümkün kılarak, yapı–aktivite ilişkisi (SAR) çalışmalarına elverişli bir platform sunmaktadır. Bu derleme, antikanser aktiviteye sahip kalkon türevlerinin sentezi ve SAR temelli optimizasyonuna ilişkin güncel gelişmeleri ele almaktadır. Sübstitüent etkileri, sterik ve elektronik açıdan çeşitli sistemlerin erişilebilirliği ile iskelet (scaffold) modifikasyonuna yönelik olanaklar dâhil olmak üzere temel sentetik hususlar tartışılmaktadır. Buna paralel olarak, yapı–fonksiyon ilişkilerinin bağlamlandırılması amacıyla tübülin bozulması, kinaz modülasyonu, apoptoz indüksiyonu ve antianjiyojenik etkiler gibi seçilmiş biyolojik mekanizmalar kısaca özetlenmektedir. Son olarak, kalkon temelli yeni nesil antikanser ajanların geliştirilmesine yön vermek amacıyla mevcut sentetik ve translasyonel zorluklar ile hibrit molekül tasarımı ve biyoizosterik modifikasyon gibi ortaya çıkan stratejiler ele alınmaktadır.

Anahtar Kelimeler

• Kalkon
• Kanser önleyici maddeler
• Claisen-Schmidt yoğunlaşması
• Yapı-aktivite ilişkisi (SAR)

Chalcones as versatile scaffolds in drug design: synthesis, structure–activity relationship (sar), and anticancer potential

Öz

Chalcones, 1,3-diaryl-2-propen-1-ones, represent a structurally simple yet highly versatile class of α, β-unsaturated carbonyl compounds that have gained considerable attention in anticancer drug discovery. The persistent emergence of drug resistance, off target toxicity, and tumor heterogeneity drives the search for tunable, multi target scaffolds, and chalcones occupy a privileged position by engaging multiple cancer-related macromolecular targets. Their modular architecture allows efficient structural diversification through well-established synthetic methodologies, most notably the Claisen–Schmidt condensation. Systematic variation of substituents on either aromatic ring provides a convenient platform for structure activity relationship (SAR) studies, enabling fine-tuning of electronic properties, molecular planarity, and physicochemical characteristics. This review highlights recent advances in the synthesis and SAR driven optimization of chalcone derivatives with anticancer activity. Particular attention is given to how substituents on rings A and B translate into changes in potency and target selectivity across breast, lung, colorectal, cervical, prostate, and hematological malignancies, supported by a comparative table linking structural features to in vitro IC₅₀ values and mechanism of action. Key synthetic considerations, including substituent effects, accessibility of sterically and electronically diverse systems, green chemistry-oriented variants of the Claisen–Schmidt condensation, and opportunities for scaffold modification, are discussed. In parallel, selected biological mechanisms such as tubulin disruption, kinase modulation, apoptosis induction, redox regulation, and antiangiogenic effects are briefly systematically summarized to contextualize structure function relationships. Finally, current synthetic and translational challenges, together with emerging strategies such as hybrid molecule design, prodrug approaches, computational SAR analysis, and bioisosteric modification, are outlined to guide the development of next generation chalcone based anticancer agents.

Anahtar Kelimeler

• Chalcone
• Anticancer agents
• Claisen–Schmidt condensation
• Structure–activity relationship (SAR)

Kaynakça

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