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However, except for alkylating DNA, nitrogen mustards may alkylate other bio-molecules to cause off-target effects due to their highly active functional groups. So, more exposure of DNA from chromosomes can facilitate the binding of nitrogen mustards to DNA to present stronger anticancer activity, simultaneously avoiding more side effects.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Objective:<\/jats:title>\n<jats:p>To design and synthesize the 4-phenylbutanoic acid-chlorambucil conjugates and valproic acid-chlorambucil conjugates. Upon cellular internalization, the two conju-gates can more strongly damage the DNA of cancer cells due to the more exposure of cel-lular DNA caused by 4-phenylbutanoic acid or valproic acid.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods:<\/jats:title>\n<jats:p>To validate this hypothesis, we designed and synthesized two hybrids of chlo-rambucil with 4-phenylbutanoic acid and valproic acid, denoted as compound 2a and compound 2b respectively. The antitumor activity of the aforementioned hybrids was evaluated by the MTT method, mitochondrial membrane potential analysis, apoptosis as-say, DNA damage assay, and scratch assay respectively.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results:<\/jats:title>\n<jats:p>Compound 2a and compound 2b were synthesized via esterification. The results of bioactivity evaluation showed compound 2a and compound 2b had stronger cytotoxici-ty against breast cancer MDA-MB-231 cells and MCF-7 cells than chlorambucil. More importantly, toward triple negative breast cancer MDA-MB-231 cells, compound 2a ex-hibited significantly greater cytotoxicity compared to both compound 2b and chlorambu-cil. Further studies were conducted on MDA-MB-231 cells, showing that compound 2a could more strongly decrease the mitochondrial membrane potential, induce cell apopto-sis, and damage cellular DNA compared to compound 2b and chlorambucil. Interestingly, in combating the migration of MDA-MB-231 cells, the results exhibited that compound 2b had a much stronger anti-migratory effect than compound 2a, inconsistent with the aforementioned in vitro cytotoxicity.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion:<\/jats:title>\n<jats:p>These findings demonstrate that the combination of nitrogen mustards with histone deacetylase inhibitors is an effective strategy to exert synergistic anti-tumor ef-fects.<\/jats:p>\n<\/jats:sec>","DOI":"10.2174\/0115701794351301241217074232","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T03:09:17Z","timestamp":1739329757000},"page":"737-746","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Conjugation of Chlorambucil with 4-Phenylbutanoic Acid and Valproic Acid respectively for Enhancing Anti-tumor Activity"],"prefix":"10.2174","volume":"22","author":[{"given":"Yi","family":"Dai","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Science, Anhui Xinhua University, Hefei 230088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of\nThe University of Science and Technology of China, Hefei, 230031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangxiang","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Anhui Xinhua University, Hefei 230088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yupei","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Anhui Xinhua University, Hefei 230088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Bai","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Anhui Xinhua University, Hefei 230088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"965","reference":[{"key":"ref=1","doi-asserted-by":"publisher","first-page":"5113","DOI":"10.1021\/acs.jmedchem.3c02476","volume":"67","author":"Li Y.","year":"2024","unstructured":"Li Y.; DNA adducts in cancer chemotherapy. 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