Optimization of the N-Lost Drugs Melphalan and Bendamustine: Synthesis and Cytotoxicity of a New Set of Dendrimer−Drug Conjugates as Tumor Therapeutic Agents

Abstract

Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.

Esters of Bendamustine Are by Far More Potent Cytotoxic Agents than the Parent Compound against Human Sarcoma and Carcinoma Cells

“…Alkyl (C 1 –C 24 ) esters of bendamustine were reported as potential prodrugs for intravenous application [ 28 ], and biodegradable polyphosphoesters were described as an approach to stabilize bendamustine in solution [ 29 ]. Another approach aimed at increasing the cytotoxicity by constructing dimeric and dendrimeric bendamustine derivatives [ 30 ].…”

Cell death‐inducing properties of selected dendrimers against different breast cancer and leukemia cell lines

“…Comparison of treated and control (solvent) cells allows statements about the cytotoxicity of administered dendrimers. [4][5][6]12,13,15] G 1 (Phe) 6 was inactive against MDA-MB-231 cells at the con- the first-generation dendrimers G 1 (Phe) 6 and G 1 (Dan) 3 , the secondgeneration dendrimer G 2 had a more pronounced impact. This is in agreement with the finding that raising the generation G n of PAMAM dendrimers is accompanied by increased cytotoxicity.…”

“…[ 3 ] The dendrons are functionalized by terminal groups, for example, amines or carboxylates, which can be used to attach bioactive compounds or to label the macromolecule by fluorescent dyes. [ 4–10 ]…”

“…Their terminal amino groups can be used to bind cytotoxic metal complexes, as shown by our group, [6] or to attach carboxylate-bearing cytostatics, for example, bendamustine or melphalan via formation of an amide bond. [5,15,16] Though dendrimers have a wide range of biomedical applications, [17][18][19] they are hampered to some extent by their cytotoxicity.…”

Nanostructures of PAMAM Dendrimers in Drug Delivery System for 5-Fluorouracil

“…When dendrimers are used as the nanocarriers, lower dosages of anticancer drugs are needed, which in turn would alleviate the side effects of the medicine [20][21][22]. Dendrimers serve as carriers for various anticancer drugs such as 5-fluorouracil [23], cisplatin [24,25], doxorubicin [26][27][28], famotidine [29], methotrexate [30], nifedipine [31], paclitaxel [32,33], 10-hydroxycamptothecin [34], 7-butyl-10-aminocamptothecin [35], etoposide [36], artemisinin [37], flutamide [38], melphalan [39], gemcitabine [40], capecitabine [41] and 6-mercaptopurine [42]. Dendrimers havealso been used against human immunodeficiency viruses(HIV) [43][44][45], Alzheimer's disease [46,47], prion diseases [48,49], inflammation [50][51][52] and bacteria [53][54][55].…”