B细胞淋巴瘤中的抗增殖筛选：加纳药用植物及其植物化学关联

Background. Lymphomas remain a major cause of morbidity and mortality, with patients relapsing due to resistance to treatment and cumulative toxicity. Over 60% of anticancer drugs are derived from plant-derived natural products (NPs) or their derivatives. NPs add 3D-rich scaffolds that broaden chemical space and engage “hard” targets. Semi-synthesis around NP cores can enhance potency, selectivity, and pharmacokinetics, preserving novel mechanisms orthogonal to current agents, which help bypass or delay resistance. Here, we have studied NPs derived from 10 Ghanaian individual plant species and 2 defined mixtures for their anti-tumor activity in marginal zone lymphoma (MZL) models, including derivatives with secondary resistance to BTK, BCL2, and PI3K inhibition. Methods. We screened 48 samples (single species, mixtures, purified compounds, fractions, extracts) in VL51, SSK41, Karpas1718parental and their resistant derivatives (VL51 ibrutinib resistant, SSK41 venetoclax resistant, and Karpas1718 idelalisib resistant) at 10 and 1 µg/mL for 72 h (MTT). Activity was defined as ≥30% inhibition of proliferation. Selected chemotypes were assigned by LC/MS-guided isolation and NMR. Results. The samples' activity was heterogeneous, with 7% of all readouts active at 1 µg/mL and 30% at 10 µg/mL. The most consistent and potent inhibition was observed for Dichapetalum heudelotii root fractions (DOS-19/20/21/22) and Xylopia aethiopica fruit fractions (DOS-34/45/47). DOS-20 contained stilbenoids including (E)-combretastatin A-1, combretastatin B-1, and heudelotols, and produced a strong and broad inhibition of proliferation at 10 µg/mL. DOS-34 and -47, enriched in ent-kaurane diterpenoids, exerted strong inhibition of proliferation at 10 µg/mL, with a clear loss of activity at 1 µg/mL, indicating a steep dose-response behavior. The single compound hexyl-9-oxodecanoate (DOS-8) exhibited higher activity at both 10 and 1 µg/mL in SSK41 venetoclax-resistant cells than in parental cells. Similarly, the single compound isomeranzin, derived from Clausena anisata , and the Xylopia + Bambusa precipitate showed higher activity in SSK41 venetoclax-resistant cells. Subfractions from column chromatography of a mixture of Aloe vera and T. officinale showed preferential activity in SSK41 cells and Karpas1718, with higher activity in Karpas1718 idelalisib-resistant cells than in parental cells. Discussion. We observed a strong chemotype-activity pattern: stilbenoids and ent-kaurane diterpenoids were the most potent profiles, while alkaloids exhibited narrower, context-specific effects; fatty ester-rich samples were mostly inactive. The sharp dose dependence of Dichapetalum and Xylopia fractions with activity in resistant and TP53-defective models suggests that they are priority leads for mechanism-of-action studies and optimization against drug-resistant B-cell lymphomas.