Improved Synthesis of Neocryptolepine-type Indoloquinolines: Applications for New Fluorescent Labelled Derivatives and Anticancer Activity Evaluations

  • Mostafa Amer

Student thesis: Master of Philosophy


Cancer is one of the leading causes of death in the world. Though advances in cancer therapy and diagnosis have considerably improved life expectancy, the overall survival rate of patients still remains poor. Disseminated cancer at the time of diagnosis and acquisition of tumour resistance are two main reasons. The growing knowledge of the biochemical pathways involved in a disease process increases the possibility to develop new approaches to treat this disease. An extremely promising strategy for cancer prevention today is chemotherapy, which is defined as the use of synthetic or natural agents (alone or combination) to block the development of cancer in humans. A major obstacle for the successful use of chemotherapy in cancer treatment is tumour cell resistance. Therefore, the need to find a safe and highly effective cure for cancer remains a major challenge for modern science. In this regard, natural products offer novel concepts in structural diversity and molecular recognition that can be used in drug design. This work describes the design and synthesis of a number of neocryptolepine analogues with selected C2 and/or C11 ring substituents. During this process, efficient synthetic methodologies have been developed for the preparation of the natural product skeleton of the neocryptolepine. The synthesis of the neocryptolepine nucleus was achieved by chlorination of methyl indole-3-carboxylate with N-chlorosuccinimide in the presence of 1,4-dimethylpiperazine, followed by the addition of N-methylaniline derivatives as a trichloro acetate salts. The resulting intermediates were cyclised in boiling diphenyl ether to give the required tetracyclic indoloquinolinone core structure of the neocryptolepine nucleus, which upon reaction with phosphorus oxychloride give the corresponding key intermediates 11-chloroneocryptolepine derivatives with large chemical diversity on the heteroaromatic nucleus. This three-step approach, starting from easily accessible intermediates, was employed for the preparation of new analogues with varied substitution patterns in good yields, short reaction times and high degree of purity. The key intermediate 11-chloroneocryptolepine derivatives were used for the diversification of the neocryptolepine core at the C-11 position. Thus, the neocryptolepine derivatives with C-11 alkyldiamine side chains and different carbon spacers between the two nitrogens were synthesized after reaction of the 11-chloroneocryptolepines with an excess of the appropriate alkyldiamine via a nucleophilic aromatic substitution reaction with release of chloride at the C-11 position. In addition, the synthesis of neocryptolepine analogues bearing a fluorescent labeling group at the terminal nitrogen of the aminoalkyamino side-chain has also been performed and their in vitro anticancer activity has been studied. Neocryptolepine derivatives with fluorescent labeling dansyl and nitrobenzofurazanyl groups were synthesized through the reaction of the terminal free amino group at the side-chain of the aminoalkylamino neocryptolepine derivatives with dansyl chloride or 4-chloro-7-nitrobenzofurazan to afford N-dansylated and N-nitrobenzofurazanylated neocryptolepine conjugates in good yields. A plausible mechanism for the formation of all intermediates as well as the end target products is discussed. Moreover, the structures of all key intermediates and final compounds have been established on the basis of 1H and 13C-NMR, 1H-1H homonuclear correlation spectroscopy (COSY) and mass spectral analysis. The potency of these synthetic analogues to inhibit cancer cell proliferation and induce cancer cell death in three different human cancer cell lines has been evaluated by colorimetric MTT assay and compared with etoposide as a reference drug. The cancer cell lines HCT116 (colorectal), SAOS (osteoclast) and MDA-MB-468 (breast) were selected due to their different sensitivities against chemotherapeutics in clinical use. All the tested compounds
Date of Award31 Dec 2016
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorJohn Gardiner (Supervisor)


  • Synthesis, Neocryptolpine, Fluorescent labelling,Anticancer

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