Liquid chromatographic analysis of the anticancer alkaloid luotonin A and some new derivatives in human serum samples

The quantitation of the natural cytotoxic and anti‐inflammatory alkaloid luotonin A and five recently synthesized derivatives is described, constituting the first report of a HPLC method for the analysis of these compounds in human serum samples. The conditions for the chromatographic separation were optimized and the method was validated for the analysis of these compounds in biological samples according to international guidelines. An RP‐HPLC method with fluorimetric detection and a C₁₈ stationary phase was applied. Different ACN/water mobile phases were assayed, including 0–4% of a mobile phase modifier such as tetrahydrofuran, dioxane or tert‐butyl methyl ether. Isocratic and gradient elution conditions are compared. The influence of pH on the efficiency and resolution of the separation was also considered. The developed method was applied to the determination of luotonins in pooled human serum samples by gradient elution RP‐HPLC using a simple cleanup procedure. The proposed chromatographic method exhibits satisfactory analytical figures of merit, with LOD from 1.0×10^?10 to 2.0×10^?10 M, intraday and interday precision below 6% except for the concentration level closest to LOD, and good agreement between experimental and theoretical concentrations. Therefore, the developed method is suitable, reliable, rapid, and simple.     

Design and synthesis of A- and D ring-modified analogues of luotonin A with reduced planarity

A small library of A- and D-ring modified luotonin-inspired heterocyclic systems have been synthesised in moderate to good yields following a six-step route that starts from phenylalanine and has the final key stage an intramolecular Povarov reaction of imines obtained from a tetrahydroquinoline-derived alkynyl aldehyde and various arylamines.     

A short and efficient general synthesis of luotonin A, B and E

Highly convergent synthesis of three luotonins (A, B, and E) has been achieved from readily available starting materials. The key step in the synthesis is formation of quinazolinone skeleton by the condensation of 3-(1,3-dioxolan-2-yl-quinoline-2-carbaldehyde and anthranilamide.     

Remarkable regioselectivities in the course of the synthesis of two new Luotonin A derivatives

Ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate reacts selectively with trimethylaluminium-activated 2-amino- or 4-aminobenzoic acid ethyl esters to give the corresponding anilides without self-condensation of the aminobenzoate building blocks. After propargylation, the quinazolinones were treated with Hendrickson's reagent, but only the para-substituted ester was found to undergo the expected [4 + 2] cycloaddition reaction, affording a new Luotonin A derivative. A different regioselectivity was observed with the ortho-substituted ester which affords a benzoxazinone under identical conditions. When the ester group in the ortho-substituted intermediate is replaced with a nitrile function, the outcome of the reaction with Hendrickson's reagent depends on the absence or presence of a base (DBU), yielding either a triphenylphosphonium-substituted iminobenzoxazine or a 4-cyano-substituted Luotonin A derivative.     

骆驼宁F一锅全合成的创新型综合实验设计及教学实践

基于天然产物骆驼宁F一锅全合成的相关科研成果,利用本科生创新型综合实验平台,设计了从简单易得的底物出发,在较温和的条件下实现天然产物骆驼宁F一锅全合成的创新型综合化学实验。该实验将自组织一锅全合成的前沿理论知识应用到骆驼宁F的全合成之中,实验内容包括文献调研及分析总结、骆驼宁F一锅全合成、化合物波谱学性质检测分析以及反应过程学研究等部分。该实验可以显著提高学生对于有机合成方法学及反应过程学研究方式的理解,使其掌握相关实验操作技术及核磁等大型仪器的检测原理和操作技能,培养学生的文献检索、路线设计、合成操作以及谱图分析等方面的综合能力,提升学生的科学研究兴趣及独立思考解决问题的创新意识。     

Synthesis of hybrids between the alkaloids rutaecarpine and luotonins A, B

The synthesis of 7,12-dihydroindolo[2′,3′:3,4]pyrrolo[2,1-b]quinazolin-5-one, a hybrid compound containing common structural features of the natural alkaloids rutaecarpine (Evodia rutaecarpa) and luotonin A (Peganum nigellastrum), was performed by active methylene group transformations of deoxyvasicinone. The synthesis of 7-hydroxy-8-norrutaecarpine was accomplished via the first total synthesis of bouchardatine (Bouchardatia neurococca) and its acid-catalyzed ring closure. The synthesized alkaloid analogues are the first representatives of a new heterocyclic ring system. Preliminary testing of the synthesized compounds showed cytotoxic activities against HeLa cells and apoptosis inducing effects at a concentration comparable to that of the control drug, etoposide.     

Toward new camptothecins. Part 7: Synthesis of thioluotonin and its 5-methoxycarbonyl derivative

The synthesis of thiodeoxyvasicinone and thioluotonin derivatives is described. The results obtained indicate that in these series, oxygen to sulfur replacement leads to absence of strong interaction with topoisomerase I-DNA.