Derivatives of nitrogen mustard anticancer agents with improved cytotoxicity

• Published in: Archiv der Pharmazie (Weinheim) Vol. 354; no. 4; pp. e2000366 - n/a
• Main Authors: Antoni, Frauke, Bernhardt, Günther
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.04.2021; Wiley Subscription Services, Inc
• Subjects: bendamustine; Cancer; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; chlorambucil; Cytotoxicity; derivatives; Life Sciences & Biomedicine; melphalan; nitrogen mustards; Pharmacology & Pharmacy; Physical Sciences; Sarcoma; Science & Technology; derivatives; PLASMA; MECHANISM; PATTERN; melphalan; nitrogen mustards; chlorambucil; CANCER; bendamustine
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000366

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. The target compounds showed cytotoxic or cytocidal effects at concentrations over 1 μM in a kinetic chemosensitivity assay. The bendamustine and 6‐isobendamustine derivatives, thus, showed clearly improved effects as compared with the parent compounds, which are ineffective against cancer cells. The chlorambucil derivatives were also much more potent than their precursor. The improved cytotoxicity may be due to increased cellular uptake via transporters. The melphalan derivatives were only slightly more potent than their parent compound, conceivably because the latter already exploits uptake transporters.