A Novel Inhibitor of Human Telomerase Derived from 10H-Indolo[3,2-b]quinoline Vittorio Caprio, a Berengere Guyen, b Yaw Opoku-Boahen, a John Mann, a,b Sharon M. Gowan, c Lloyd M. Kelland, c Martin A. Read d and Stephen Neidle d, * a Chemistry Department, Reading University, Whiteknights, Reading RG6 6AD, UK b School of Chemistry, Queen’s University Belfast, Belfast BT9 5AG, UK c CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK d CRC Biomolecular Structure Unit, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK Received 19 April 2000; revised 23 June 2000; accepted 27 June 2000 Abstract—The bis-dimethylaminoethyl derivative of quindoline (10H-indolo[3,2-b]quinoline), an alkaloid from the West African shrub Cryptolepis sanguinolenta, has been synthesised. This has been shown to have modest cytotoxicity, as well as inhibitory activity against the telomerase enzyme. It is hypothesised that the latter activity is due to stabilisation of an intermediate guanine- quadruplex complex, in accordance with computer modelling. # 2000 Elsevier Science Ltd. All rights reserved. The specialised DNA sequences at the ends of chromo- somes comprise tandem repeats of simple oligonucleotide sequences. The telomeric repeat in vertebrates, including humans, is 5 0 -TTAGGG. 1,2 Telomeres have a number of functions including protection of the ends of chromosomes from degradation and recombination, and an involvement in control of senescence, replication and the cell cycle clock. 3 In normal cells, successive rounds of cell division are accompanied by telomere shortening, by around 50–200 nucleotides per division, due to the inability of DNA polymerase to fully repli- cate the ends. In cancer cells, although the telomeres are typically shorter than those of normal (or of germ-line) cells, their length is maintained by addition of telomere repeat sequences, a process catalysed by the enzyme telomerase. 4 This enzyme is also directly implicated in the immortalisation of cancer cells, and it is significant that around 85–90% of human tumours possess telo- merase activity while somatic cells invariably lack the enzyme 5 (although stem cells, which tend to have long telomeres, do have significant telomerase activity). The possibility of designing drugs with inhibitory activity against telomerase is emerging as an attractive strategy for cancer chemotherapy. 6 It is proposed that telomerase inhibition would result in progressive telomere shortening in tumour cells over a number of generations, leading to selective inhibition of tumour cell growth. This has now been demonstrated using (i) PNA antisense molecules targeted against the RNA template of telomerase, 7 and (ii) with telomerase dominant negative mutants. 8 We have developed an approach to the rational design of telomerase inhibitors which has involved the folding of the single-stranded telomere primer into four-stranded quadruplex structures; 9 these cannot be substrates for the enzyme. Folding has been achieved with a range of small molecules, sharing the structural features of a planar electron-deficient chromophore and basic side chain(s), including derivatives of amido-substituted tri- cyclic anthraquinones, fluorenones and acridines. 10 Molecular modelling 11 and other biophysical studies 12 have shown that these molecules bind to G-quad- ruplexes, and that strength of binding correlates with extent of telomerase inhibition. The original discovery that forms the basis for the work described here, arises from studies on the West African shrub Cryptolepis sanguinolenta. This has a long asso- ciation with Ghanaian folk medicine, and is prized for its use in the treatment of fevers, including malaria, and for the control of infections of the urinary and upper respiratory tracts. 13 During the past few years, the major alkaloidal constituent, cryptolepine 1 (Fig. 1) has been the object of numerous biological studies, and the medicinal value of the plant has been fully substantiated. 0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(00)00378-4 Bioorganic & Medicinal Chemistry Letters 10 (2000) 2063–2066 *Corresponding author. Tel.: +44-020-7970-6043; fax: +44-020-7352- 8039; e-mail: s.neidle@icr.ac.uk