Hemiasterlin (Hem) and dolastatin (Dol) are marine natural products which are cytotoxic for cancer cells. Hem, a tripeptide, and Dol, a hexapeptide, were conjugated with linkers (L) to the universal BB agonist DPhe-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2(BA1) and the effects of the Hem-BB and Dol-BB conjugates investigated on NCI-H1299 lung cancer cells. Hem-LA-BA1 and Hem-LB-BA1 inhibited specific (125I-Tyr4)BB binding to NCI-H1299 cells, which have BB2 receptors (R), with IC50 values of 15 and 25 nM, respectively. Addition of Hem-LA-BA1 and Hem-LB-BA1 to Fura-2 AM loaded cells containing BB2R, caused elevated cytosolic Ca2+. In a growth assay, Hem-LA-BA1 and Hem-LB-BA1 inhibited the proliferation of NCI-H1299 cells. Dol-succinamide (Dols)-LD-BA1 and Dols-LE-BA1 bound with high affinity to NCI-H1299 cells and elevated cytosolic Ca2+, but did not inhibit the proliferation of NCI-H1299 cells. Also, Hem-LA-BA1 inhibited 125I-DTyr-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2 (BA2) binding to Balb/3T3 cells transfected with BB1R or BB2R as well as with BRS-3 with IC50 values of 130, 8, and 540 nM, respectively. These results show that Hem-BB conjugates are cytotoxic for cancer cells containing BB2R.

Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents.Keywords 5-Aza-ellipticine; Anti-tumor agents; Topoisomerase II; Ellipticine Ellipticine (1) was first identified in 1959 as a compound in the leaves of an Australian evergreen, Ochrosia elliptica labil (Apocynaceae family). 1 Ellipticine is one of many carbazole alkaloids that exhibit biological, especially anti-tumor, activities. 2 Many synthetic variants of the natural product were made and tested for anti-tumor activity. The most likely target of ellipticine is topoisomerase II, whose inhibition results in the observed cytotoxicity. However, the low water solubility of ellipticine at physiological pH, as well as its systemic toxicity, prevents its use as a therapeutic agent. Several simple structural modifications to ellipticine derivatives gave compounds with increased toxicity (such as a methoxy substituent at the C9 position and a methyl substituent at the C11 position). 3,4Previously, the novel ellipticine derivative (2) was coupled to heptagastrin, which binds with high affinity to the gastrin/cholecystokinin type B receptor. 5 The hypothesis was that since CCK-B receptors are over-expressed in some gastrointestinal cancers, 6 the heptagastrin conjugate could be delivered very selectively to CCK-B positive cancer cells by receptormediated endocytosis. We demonstrated that heptagastrin conjugate was delivered to lysozomes in CCK-B receptor positive cells where it was processed to release the cytotoxic ellipticine derivative. Compound 2 is cytotoxic to tumor cells at low nanomolar concentrations but is relatively nonselective, while the heptagastrin conjugate, while slightly less toxic to sensitive cells, was completely selective to only those cells that expressed the CCK-B receptor. Compound 2 was synthesized in thirteen steps with an overall 7% yield. Recently, Zhang et al. 7 reported the synthesis of 5-aza analogues of ellipticines (3) via an interesting radical cyclization reaction. We wished to examine the anti-tumor properties of these novel compounds because their synthesis was more readily accomplished than the original ellipticines and because they offered the possibility of additional elaboration of the original structures. In this study, novel 5-aza-ellipticine derivatives were synthesized, which contain a C9 methoxy substituent and a C11 methyl substituent. Consistent with known structure-activity relationships of ellipticine, many of these novel 5-aza-ellipticine derivatives inhibited the growth of HCT116 cells, with approximately the same potency as ellipticine.The synthesis of the 1-chloro-5-aza...

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Alkaloids U 0600Synthesis and Biological Activity of 5-Aza-ellipticine Derivatives. -A series of title compounds is prepared and shown to be a new class of antitumor agents, though they are not as biologically active as their corresponding ellipticine analogues. Compound (VI) (yield not given) is equally potent as ellipticine against HCT116 colon cancer cells in vitro and is a more potent catalytic inhibitor of topoisomerase II. -(MOODY, D. L.; DYBA, M.; KOSAKOWSKA-CHOLODY, T.; TARASOVA*, N. I.; MICHEJDA, C.