Computer-aided design, synthesis, and biological studies of anticological nitrogen-containing tetraphosphonic acids against melanoma

• Published in: Monatshefte für Chemie Vol. 149; no. 8; pp. 1481 - 1491
• Main Authors: Bekheit, Mohamed S., Barghash, Reham F., Abdou, Wafaa M.
• Format: Journal Article
• Language: English
• Published: Vienna Springer Vienna 01.08.2018; Springer Nature; Springer Nature B.V
• Subjects: Acids; Analytical Chemistry; Anticancer properties; Biological properties; CAD; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Computer aided design; Imines; Inorganic Chemistry; Melanoma; Molecular chains; Organic Chemistry; Original Paper; Physical Chemistry; Physical Sciences; Reagents; Science & Technology; Skin cancer; Theoretical and Computational Chemistry; Bis(α-aminobisphosphonic acids); Structure activity relationship; Pudovik reaction; Malignant melanoma; TEREPHTHALIC SCHIFF-BASES; STEREOCHEMICAL BEHAVIOR; Bis(alpha-aminobisphosphonic acids); OSTEOCLASTS IN-VITRO; DRUG DISCOVERY; NATIONAL-CANCER-INSTITUTE; CELL-LINES; DIARYL PHOSPHITES; BREAST-CANCER; CONTAINING BISPHOSPHONATES; MULTIDRUG-RESISTANCE
• ISSN: 0026-9247; 1434-4475
• DOI: 10.1007/s00706-018-2196-9

As a part of our quest to develop new bioactive bisphosphonic acids, we synthesized a series of bis(α-aminobisphosphonic acids) in good yields (66–78%) as new entities for treating malignant melanoma. The reaction of the Schiff bases, 1,4-pheneylenediimines with the Horner–Emmons–Wadsworth reagent, tetraethyl methylene-1,1-bisphosphonate in DMF/LiOH (aq) solution led exclusively to a meso form of nitrogen-containing tetraphosphonates (NTPs) (bis(α-aminobisphosphonates)). Next, hydrolysis of the ester moieties of the tetraphosphonate products yielded the corresponding tetraphosphonic acids, which treated with MeOH/KOH (aq, 20%) to give the respective NTP-tetrapotassium salts. Prior to synthesis, the suggested structures (and others) were applied to the computer-assisted molecular modeling, PASS program to investigate their prospective biological properties. Cytotoxic properties were later evaluated against five malignant melanoma cell lines that originated from different categories of malignant melanoma primary stage (I/II), histologically advanced stage (III/IV), and metastasized malignancy. Almost all tested compounds showed antitumor activity though on different levels. Three NTP salts were found to have activity in the range of GI 50 0.650–5.73 μM vs. control reference GI 50 : 1.745–6.50 μM. Structure activity relationship is also discussed. Graphical abstract