Biophysical Chemistry Laboratory, Physical Chemistry Section, Department of Chemistry, Jadavpur University, 188 Raja S. C. Mallick Road, Kolkata 700032, India.
Biophysical Chemistry Laboratory, Physical Chemistry Section, Department of Chemistry, Jadavpur University, 188 Raja S. C. Mallick Road, Kolkata 700032, India.
Biochim Biophys Acta Gen Subj. 2021 Nov;1865(11):129993. doi: 10.1016/j.bbagen.2021.129993. Epub 2021 Aug 25.
Low pH induced nucleic acid polymorphism and the interaction of naturally occurring small molecules with different polymorphic forms of DNA have been the focus in developing new drugs. Recent studies have revealed that low pH plays an active role in growth and development of cancer cells. Our target is to find whether and how the indoloquinoline alkaloid cryptolepine (CRP) interact with different polymorphic forms of natural DNA, in hope to explore this group of alkaloids as new therapeutics.
Multiple spectroscopic techniques that include UV-visible absorption spectrophotometry, fluorimetry, CD spectroscopy along with thermal melting studies were employed to characterize the interaction between the alkaloid cryptolepine with the B and protonated forms of DNA.
RESULTS & CONCLUSIONS: Cryptolepine has been found to interact with either forms of DNA. The nature of binding is non-cooperative in both cases. Data show that the affinity of CRP to B form of DNA is relatively higher than that for the protonated form of DNA. Circular dichroic studies reveal that the alkaloid converts the left handed protonated DNA into bound right handed form. Fluorescence quenching experiments reveal that cryptolepine intercalates within the DNA base pairs. Thermal melting studies show that the alkaloid stabilises the DNA structures.
Such non-B DNA structures are often present at the 'mutation hotspots' that are associated with genetic instability related diseases such as cancer. The ability of cryptolepine to interact to such non-B DNA structures makes it a useful substrate in the designing of potential chemotherapeutic agents.
低 pH 值诱导核酸多态性，以及天然存在的小分子与不同多态形式的 DNA 之间的相互作用，一直是开发新药的重点。最近的研究表明，低 pH 值在癌细胞的生长和发育中发挥着积极的作用。我们的目标是确定 indoloquinoline 生物碱 cryptolepine（CRP）是否以及如何与天然 DNA 的不同多态形式相互作用，希望探索这组生物碱作为新的治疗方法。
采用多种光谱技术，包括紫外-可见吸收分光光度法、荧光光谱法、圆二色光谱法以及热融研究，来表征生物碱 cryptolepine 与 B 型和质子化形式的 DNA 之间的相互作用。
发现 cryptolepine 与两种形式的 DNA 都发生相互作用。在这两种情况下，结合的性质都是非协同的。数据表明，CRP 与 B 型 DNA 的亲和力相对高于与质子化形式 DNA 的亲和力。圆二色性研究表明，生物碱将左手质子化的 DNA 转化为结合的右手形式。荧光猝灭实验表明 cryptolepine 在内切碱基对中嵌入。热融研究表明，生物碱稳定了 DNA 结构。
这种非 B 型 DNA 结构通常存在于与遗传不稳定性相关疾病（如癌症）相关的“突变热点”中。cryptolepine 能够与这种非 B 型 DNA 结构相互作用，使其成为设计潜在化疗药物的有用底物。
