Osella María I, Salazar Mario O, Solís Carlos M, Furlan Ricardo L E
Consejo Nacional de Investigaciones Científicas y Técnicas, Suipacha 531, S2002LRK, Rosario, Argentina.
Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina.
Nat Prod Bioprospect. 2025 Jan 5;15(1):4. doi: 10.1007/s13659-024-00488-2.
Chemically engineered extracts represent a promising source of new bioactive semi-synthetic molecules. Prepared through direct derivatization of natural extracts, they can include constituents enriched with elements and sub-structures that are less common in natural products compared to drugs. Fourteen such extracts were prepared through sequential reactions with hydrazine and a fluorinating reagent, and their α-glucosidase inhibition properties were compared. For the most bioactive mixture, a chemically modified propolis extract, enzyme inhibition increased 22 times due to the reaction sequence. Bio-guided fractionation led to the isolation of a new fluorinated pyrazole produced within the extract by chemical transformation of the flavonoid chrysin. The inhibitor results from the action of the two reagents used on four common functional groups present in natural products (carbonyl, phenol, aromatic carbon, and a double bond). The reactions led to the opening of a 6-member oxygenated heterocycle to produce a 5-member nitrogenated one, as well as the dehydroxylation and fluorination in two different positions of one of the aromatic rings of the natural starting material, all within a complex mixture of natural products. Overall, these transformations led to an approximately 20-fold increase in the α-glucosidase inhibition by the isolated inhibitor compared to its natural precursor.
化学工程提取物是新型生物活性半合成分子的一个有前景的来源。通过对天然提取物进行直接衍生化制备而成，它们可能包含富含某些元素和亚结构的成分，这些元素和亚结构在天然产物中相对于药物而言不太常见。通过与肼和一种氟化试剂进行顺序反应制备了14种这样的提取物，并比较了它们对α-葡萄糖苷酶的抑制特性。对于活性最高的混合物，即一种化学修饰的蜂胶提取物，由于反应顺序，酶抑制作用提高了22倍。生物导向分级分离导致从提取物中分离出一种新的氟化吡唑，它是由黄酮类化合物白杨素经化学转化产生的。该抑制剂是由所用的两种试剂作用于天然产物中存在的四个常见官能团（羰基、酚羟基、芳族碳和双键）而产生的。这些反应导致一个六元含氧杂环开环，生成一个五元含氮杂环，同时天然起始原料的一个芳环的两个不同位置发生脱羟基和氟化反应，所有这些反应都发生在天然产物的复杂混合物中。总体而言，与天然前体相比，这些转化使分离出的抑制剂对α-葡萄糖苷酶的抑制作用提高了约20倍。
