Derivatives of nitrogen mustard anticancer agents with improved cytotoxicity

Abstract

In previous studies, we demonstrated that esters of bendamustine containing a basic moiety are far more cytotoxic anticancer agents than their parent compound and that the substitution of the labile ester moiety by a branched ester or an amide markedly increases stability in the blood plasma. In the current study, we showed that this substitution was bioisosteric. Aiming at increased cytotoxicity, we introduced the same modification to related nitrogen mustards: 6‐isobendamustine, chlorambucil, and melphalan. The synthesis was accomplished using the coupling reagents N,N′‐dicyclohexylcarbodiimide or 2‐(1H‐benzotriazole‐1‐yl)‐1,1,3,3‐tetramethylaminium tetrafluoroborate. Cytotoxicity against a panel of diverse cancer cells (carcinoma, sarcoma, and malignant melanoma) was assessed in a kinetic chemosensitivity assay. The target compounds showed cytotoxic or cytocidal effects at concentrations above 1 µM: a striking enhancement over bendamustine and 6‐isobendamustine, both ineffective against the selected cancer cells at concentrations up to 50 µM, and a considerable improvement over chlorambucil, showing some potency only against the sarcoma cells. Melphalan was almost as effective as the target compounds—derivatization only provided a small improvement. The novel cytostatics are of interest as model compounds for analyzing a correlation between cytotoxicity and membrane transport and for the treatment of malignancies.

Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan: Synthesis and Effects on Neuroblastoma Cells

“…N-mustards—not only M [ 14 ]—played a pivotal role in the development of chemotherapy for cancer [ 40 , 41 , 42 , 43 , 44 , 45 ]. Their development is continuing at a considerable pace [ 46 , 47 , 48 , 49 , 50 , 51 ]. The present study contributes its share to this field.…”

The Catalyst’s Companion: N,N′-Dicyclohexylcarbodiimide (DCC) in Action

“…(C) According to Antoni and Bernhardt, DCC is used as a coupling reagent for producing bendamustine ester. 11 Since bendamustine is generally given intravenously, there have been a few patent claims for formulations that could be taken orally. Additionally, it has been demonstrated that the esterification process of the carboxylic acid moiety improves the hydrolytic stability of the N-lost moiety (due to many causes), which may increase the likelihood of oral administration.…”

“…The bendamustine ester 13 was made with the use of the coupling reagent N , N ′-dicyclohexylcarbodiimide (DCC), and for the synthesis of the new bendamustine amide 14 , the coupling reagents 2-(1 H -benzotriazole-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU­) and N , N ′-diisopropylethylamine (DIPEA) were consumed. 11…”

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

“…The study was performed using three models of hematological malignancy: RPMI8226 (myeloma cancer cells), THP1 (acute monocytic leukemia cells), and HL60 (promyelocytic leukemia cells). Modification of the carboxyl group by esterification of the compound showed the highest efficacy, and the results indicated that the ester group is necessary to increase the cytotoxic activity of melphalan [ 142 , 143 ]. In vitro studies conducted by this group of researchers showed that new MEL analogues have better antitumor activity than the parent drug.…”