Development of novel naphthalimide derivatives and their evaluation as potential melanoma therapeutics

• Published in: European journal of medicinal chemistry Vol. 46; no. 8; pp. 3331 - 3338
• Main Authors: Sk, Ugir Hossain, Prakasha Gowda, A.S., Crampsie, Melissa A., Yun, Jong K., Spratt, Thomas E., Amin, Shantu, Sharma, Arun K.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.08.2011; Elsevier
• Subjects: Animals; Annexin A5 - analysis; anti-Tumor; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Flow Cytometry; General aspects; Humans; Hydrophobic and Hydrophilic Interactions; Injections, Intraperitoneal; Isothiocyanate; Isothiocyanates - chemistry; Life Sciences & Biomedicine; Medical sciences; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Mice; Mice, Nude; Naphthalimide; Naphthalimides - chemical synthesis; Naphthalimides - pharmacology; Naphthalimides - therapeutic use; Neoplasm Transplantation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Structure-Activity Relationship; Thiourea; Thiourea - chemistry; Isothiocyanate; Thiourea; Naphthalimide; anti-Tumor; Melanoma; Apoptosis; PHENETHYL ISOTHIOCYANATE; NITRIC-OXIDE SYNTHASE; MALIGNANT-MELANOMA; BENZYL ISOTHIOCYANATE; ANTITUMOR-ACTIVITY; HUMAN HEPATOMA-CELLS; POOR SURVIVAL; ACETYLCYSTEINE CONJUGATE SUPPRESS; ARYLALKYL ISOTHIOCYANATES; PHASE-I; Antineoplastic agent; Human; Nitro compound; Rodentia; Thioureas; Biological activity; Imide; Vertebrata; Mammalia; Cell line; Mouse; Animal; Organic isothiocyanate; Malignant melanoma; Chemical synthesis; Tumor cell
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.04.058

Synthesis and anti-melanoma activity of various naphthalimide analogs, rationally modified by introducing isothiocyanate (ITC) and thiourea (TU) functionalities, found in well-known anti-cancer agents, is described. The structure–activity relationship comparison of the novel agents in inhibiting cancer cell growth was evaluated in various melanoma cell lines. Both ITC and TU analogs effectively inhibited cell viability and induced apoptosis in various human melanoma cells. Nitro substitution and increase in alkyl chain length, in general, enhanced the apoptotic activity of ITC derivatives. All the new compounds were well tolerated when injected intraperitoneal (i.p.) in mice at effective doses at which both the ITC and TU derivatives inhibited melanoma tumor growth in mice following i.p. xenograft. The nitro substituted naphthalimide–ITC derivative 3d was found to be the most effective in inducing apoptosis, and in inhibiting melanoma cell and tumor growth. [Display omitted] ► Naphthalimide analogs with isothiocyanate and thiourea functions are reported. ► Increase in alkyl chain length and nitro substitution enhanced the potency. ► Six carbon alkyl chain compound 3c and nitro substituted 3d were most cytotoxic. ► Compounds 3c and 3d were most effective in inducing apoptosis in melanoma cells. ► Compounds 3c and 3d inhibited melanoma tumor growth without any systemic toxicity.