摘要 |
Disclosed is a protein-camptothecin conjugate according to the formula X-B1-B2-B3-B4-Z wherein: X is selected from camptothecin or a camptothecin derivative; Each of B1, B2, B3 and B4 is independently for each occurrence (Doc)m, (Aepa)n, -(C(O)-A1-A2-A3-A4-A5-C(O))s- or (amino acid)p; wherein the amino acid is selected from the group consisting of Gly, Val, Abu, Gaba, Doc, and Sar; each of A1 and A5 is, for each occurrence, CH2; each of A2, A3, and A4 is, independently for each occurrence, CH2 or (CH2)t or absent; integers m, n, p, s and t are as described in the specification; and Z is a peptide selected from the list of -Lys-DTyr-DTyr-cyclo(Cys-Tyr-DTrp-Lys-Abu-Cys)-Thr-NH2 ; -DPhe-cyclo(Cys-Tyr-DTrp-Lys-Abu-Cys)-Thr-NH2 ; -DPhe-cyclo(Cys-3ITyr-DTrp-Lys-Val-Cys)-Thr-NH2; -Gln-Trp-Ala-Val-betaAla-His-Leu-Leu-NH2 ; -DPhe-Gln-Trp-Ala-Val-betaAla-His-Leu-Leu-NH2 ; -Gln-Trp-Ala-Val-betaAla-His-Leu-Nle-NH2 ; -DCys-3Pal-DTrp-Lys-DCys-Thr-Tyr-NH2; and -pGlu-His-Trp-Ser-Tyr-DLys[Nepsilon~]-Leu-Arg-Pro-Gly-NH2; or a pharmaceutically acceptable salt thereof. In particular the conjugated protein may be a somatostatin, LHRH or bombesin analogue. The compounds disclosed are useful as targeted cytotoxic agents. Also disclosed herein are intermediates for the production of compounds of formula (I).
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