Design,Synthesis And Bioactivity Evaluation Of Organelle Targeted Polyamine Conjugates Based On Naphthalimide

Polyamines(putrescine,spermidine and spermidine)are a group of compounds containing two or more amino acids that are widely found in living organisms and regulate a variety of important life processes in the human body,such as ageing,immunity and cancer.Tumour cells have a high demand for polyamines due to their excessive proliferation.By coupling anti-tumour drugs with polyamines to prepare polyamine adducts,the use of polyamine transporter proteins,which can be targeted to cancer cells that are actively dividing,can achieve targeted drug delivery.Naphthalimides(benzo[c,d]indol-2(H)-ones)are a class of compounds structurally similar to naphthalimides with good fluorescent properties and important physiological activities.Early research found that this class of compounds is a typical DNA intercalator.In 2018,we discovered for the first time that the "naphthalene lactam-polyamine" conjugate is a bifunctional compound: it can not only use the polyamine transport system to target tumor cells and inhibit tumor metastasis;Enzymes,rather than the conventionally reported entry into the nucleus.Pharmacological mechanism analysis showed that it can promote apoptosis by inducing autophagy,suggesting that its structural modification may change its target.In the present work,the previously discovered "naphthalenolactam-polyamine" adducts were used as the precursors for further structural modifications and modifications: the amine group of the lactam and the naphthalene ring-4 position were modified by double substitution,focusing on the methylene ring as the linking chain between the aromatic ring and the polyamine.28 doubly substituted "naphthalenolactampolyamine" adducts were synthesized,none of which had been reported,and their structures were confirmed by 1H NMR,13 C NMR and MS techniques.Three types of six tumour cells(triple negative breast cancer cells MDA-MB-231 and breast cancer cells MCF-7;colon cancer cells HCT-116 and HT29;liver cancer cells Hep G2 and SNU739)were selected and 14 compounds were tested for their in vitro antitumour activity against these six cells by MTT assay,and another 14 compounds were tested for their in vitro antitumour activity against breast cancer cells MCF-7,liver cancer cells Hep G2 and SNU739.Seven compounds were found to have superior or comparable activity compared to the precursors(～5-6 μM)against HCT116 and Hep G2,with four of them showing a broader spectrum of inhibitory activity against six tumour types,particularly against refractory triple-negative breast cancer.It can be concluded from the results that as the alkyl side chains change,the distribution of the compounds within the organelles changes,and when the alkyl side chains are short,the distribution is similar to the distribution of the compounds within the organelles before the modification,with lysosomal aggregation and similarities in the mechanisms of action.When the alkyl side chain is medium to long,the distribution of the compound changes,with a cell membrane distribution and a change from lysosomal aggregation to mitochondrial aggregation,exhibiting a multi-targeting character.When the alkyl side chain is a long chain,the cell membrane distribution weakens and lysosomal aggregation reappears in the cell.