Design, Synthesis and Cytotoxicity of Novel Chalcone Analogs Derived from 1-Cyclohexylpyrrolidin-2-one and 2,3-Dihydrobenzo[f]chromen-1-one

• Published in: Archiv der Pharmazie (Weinheim) Vol. 345; no. 5; pp. 341 - 348
• Main Authors: Brien, Kimberly A., Bandi, Ravi Kumar, Behera, Ajaya Kumar, Mishra, Bijay Kumar, Majumdar, Poulomi, Satam, Vijay, Savagian, Mia, Tzou, Samuel, Lee, Megan, Zeller, Matthias, Robles, Andrew J., Mooberry, Susan, Pati, Hari, Lee, Moses
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 01.05.2012; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Benzochromanone; Cell Line, Tumor; Cell Survival - drug effects; Chalcones; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chromones - chemistry; Cyclohexanes - chemistry; Cytotoxicity; Drug Design; Humans; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Physical Sciences; Pyrrolidinones - chemistry; Science & Technology; Structure-Activity Relationship; Tubulin; X-ray; X-Ray Diffraction; SUBSTITUTED CHALCONES; CELLS; Benzochromanone; ANTINEOPLASTIC AGENTS; A-4; Cytotoxicity; 2-ARYLIDENEBENZOCYCLOALKANONES; COMBRETASTATIN-A4; Chalcones; POTENT; Tubulin; GROWTH; X-ray; INHIBITORS; DERIVATIVES
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201100265

Two divergent series of novel chalcone analogs, one derived from 1‐cyclohexylpyrrolidin‐2‐one and the other derived from 1‐benzo[f]chromanone, were designed, synthesized and evaluated for cytotoxicity against two murine cancer cell lines. Two 1‐benzo[f]chromanone analogs, 4g and 4j yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with IC50 values between the range of 5 and 6 µM. With an IC50 value of 3.4 µM, compound 4g was also active against human MDA‐MB‐435 melanoma cells. X‐ray structures of the β‐hydroxy ketone product (4a) and the α,β‐unsaturated ketone (4h) were collected, and confirm the syn‐configuration between the carbonyl moiety and the β‐vinylic proton in 4h. X‐ray structures of two 1‐cyclohexylpyrrolidin‐2‐one derivatives were also obtained, and both showed an E‐configuration for the double bond. Twenty‐four chalcone analogs and one aldol product derived from 1‐benzo[f]chromanone and N‐cyclohexylpyrrolidinone were synthesized and tested for cytotoxicity against murine cancer cells B16 and L1210. One 1‐benzo[f]chromanone derivative (4g), containing a 3,4,5‐trimethoxy benzylidene moiety, was quite active also against human MDA‐MB‐435 melanoma cells. The structure and conformation of the target compounds were ascertained by single crystal X‐ray analysis of four compounds.