The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anti-cancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs towards ROS was determined by measuring DNA interstrand crosslinks and/or DNA alkylations. These compounds showed 60–90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H2O2-activated anticancer prodrugs.
Reducing host toxicity is one of
the main challenges of cancer chemotherapy. Many tumor cells contain
high levels of ROS that make them distinctively different from normal
cells. We report a series of ROS-activated aromatic nitrogen mustards
that selectively kill chronic lymphocytic leukemia (CLL) over normal
lymphocytes. These agents showed powerful DNA cross-linking abilities
when coupled with H2O2, one of the most common
ROS in cancer cells, whereas little DNA cross-linking was detected
without H2O2. Consistent with chemistry observation,
in vitro cytotoxicity assay demonstrated that these agents induced 40–80%
apoptosis in primary leukemic lymphocytes isolated from CLL patients
but less than 25% cell death to normal lymphocytes from healthy donors.
The IC50 for the most potent compound (2)
was ∼5 μM in CLL cells, while the IC50 was
not achieved in normal lymphocytes. Collectively, these data provide
utility and selectivity of these agents that will inspire further
and effective applications.
A new cembranolide, capillolide (1), and three known cembranolides were isolated from the soft coral Sinularia capillosa collected from the South China Sea. Their structures and the relative stereochemistry of 1 were deduced on the basis of spectroscopic methods.
Two nitroimidazole modified thymidines 1a and 1b have been synthesized and incorporated into DNA oligomers. The 350 nm photolysis of 1a and 1b generated a 5-(2′-deoxyuridinyl)methyl radical that induced DNA interstrand cross-links (ICL). Higher ICL yield was observed under hypoxic conditions than aerobic conditions. The photoproducts of monomers or DNA oligomers were isolated and characterized by NMR and/or mass spectroscopy.
Four novel photoactivated binitroimidazole prodrugs were synthesized. These agents produced DNA interstrand cross-links (ICLs) and direct strand breaks (DSB) upon UV irradiation, whereas no or very few DNA ICLs and DSBs were observed without UV treatment. Although these four molecules (1-4) contain the same binitroimidazole moiety, they bear four different leaving groups, which resulted in their producing different yields of DNA damage. Compound 4, with nitrogen mustard as a leaving group, showed the highest ICL yield. Surprisingly, compounds 1-3, without any alkylating functional group, also induced DNA ICL formation, although they did so with lower yields, which suggested that the binitroimidazole moiety released from UV irradiation of 1-3 is capable of cross-linking DNA. The DNA cross-linked products induced by these compounds were completely destroyed upon 1.0 M piperidine treatment at 90 °C (leading to cleavage at dG sites), which revealed that DNA cross-linking mainly occurred via alkylation of dGs. We proposed a possible mechanism by which alkylating agents were released from these compounds. HRMS and NMR analysis confirmed that free nitrogen mustards were generated by UV irradiation of 4. Suppression of DNA ICL and DSB formation by a radical trap, TEMPO, indicated the involvement of free radicals in the photo reactions of 3 and 4 with DNA. On the basis of these data, we propose that UV irradiation of compounds 1-4 generated a binitroimidazole intermediate that cross-links DNA. The higher ICL yield observed with 4 resulted from the amine effector nitrogen mustard released from UV irradiation.
A photoinduced vicinal difluoroalkylation and aminosulfonylation of alkynes under photocatalysis was realized. The combination of ethyl 2-bromo-2,2-difluoroacetate, alkynes, and DABCO⋅(SO ) with hydrazines, catalyzed by 9-mes-10-methyl acridinium perchlorate in the presence of visible light, afforded (E)-ethyl 2,2-difluoro-4-aryl-4-sulfamoylbut-3-enoates in good yields with high stereoselectivity. This four-component reaction proceeds through radical addition with the insertion of sulfur dioxide.
O x i d a t i o n o f P r i m a r y A m i n e s t o N i t r i l e s w i t h T r i c h l o r o i s o c y a n u r i c A c i d Fen-Abstract: An efficient and highly selective method for the oxidative conversion of primary amines to the corresponding nitriles using trichloroisocyanuric acid in the presence of catalytic TEMPO under mild reaction conditions is described. Other functional groups such as C,C-double bonds, benzyloxy etc. were found to be unaffected under the reaction conditions. This procedure provides a new entry to the synthesis of various aliphatic, aromatic and heterocyclic nitriles in excellent yield.
A photocatalyzed transformation from sulfinic acids to sulfoxides under visible-light irradiation in the presence of Nheterocyclic carbene is established. Various alkyl groups from four-substituted Hantzsch esters or Meyer nitriles are smoothly converted to the corresponding sulfoxides through a radical coupling pathway in the presence of 1,1-carbonyldiimidazole. This method allows sulfoxide synthesis to refrain from relying on the oxidation of sulfides and provides an alternative route for the preparation of sulfoxides.
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