Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi

Design, synthesis, and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin

“…The hybrid molecules must preserve both the antineoplastic and specific binding character of their respective components. To create targeted BN-like cytotoxic agents, we linked DOX-14-Ohemiglutarate to the N terminal of pseudooctapeptide BN-(7-14) and pseudononapeptide BN- (6)(7)(8)(9)(10)(11)(12)(13)(14) analogs previously developed at our institute. The pseudooctapeptide carriers lack the bulky hydrophobic D-amino acids such as D-Phe or D-Tpi at position 6 of BN-(6-14) analogs.…”

“…Pseudononapeptide and pseudooctapeptide BNlike peptide carriers were synthesized as described (12)(13)(14)(15)(16). Cytotoxic conjugates of these peptides with DOX or 2-pyrrolino-DOX were prepared by an improvement of the procedure reported earlier for the formation of cytotoxic luteinizing hormone-releasing hormone conjugates (35).…”

“…The putative role of BN-like peptides as autocrine growth factors for these tumors (5-9) prompted researchers to design and synthesize antagonists of BN and GRP in hope of finding a different approach for the treatment of certain cancers (10)(11)(12)(13)(14)(15)(16). Over the past few years, we have developed a series of powerful BN antagonists (12)(13)(14)(15)(16). One of these antagonists (RC-3095 ϭ B 1 , Table 1) showed promising tumor inhibitory effects in various animal cancer models and in nude mice bearing xenografts of human cancer cell lines and is presently undergoing clinical trials.…”

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

“…BW2258U89 was reported to inhibit small cell lung cancer growth (Moody et al, 1995b) and to inhibit bombesin-stimulated gastrin release in vivo in dogs and rats and blocked the satiety effect of bombesin in rats (Kirkham et al, 1994). An additional series of substituted pseudopeptide analogs with position 14 substitutions in addition to the 13-14 bond have been described and widely used by Schally's group for inhibition of various tumor cell growth (Radulovic et al, 1991a;Cai et al, 1992Cai et al, , 1994Qin et al, 1994Qin et al, , 1995Jungwirth et al, 1998;Bajo et al, 2004). Two analogs with high potency in this group include [D-Phe 6 ,13-14, Tac 14 ]Bn 6 -14 (tac ϭ thiazolidine-4-carboxylic acid) (RC-3950-II) ) (K i 0.078 nM, murine BB 2 receptor) and [D-Tpi 6 ,13-14]bombesin 6 -14 (RC-3095) (K i 0.92 nM, murine BB2 receptor) Qin et al, 1994Qin et al, , 1995.…”

Bombesin induces a reduction of somatostatin inhibition of adenylyl cyclase activity, Gi function, and somatostatin receptors in rat exocrine pancreas

“…The pancreas was removed and trimmed free of fat, connective tissue, and lymph nodes. (6 -14) or RC-3095, originally synthesized by Radulovic et al [40] and Cai et al [6], was provided by Asta Pharma (Frankfurt/M, Germany). Tpi [2,3,4,9,-tetrahydro-1H-pyrido(3,4-b)indol-3-carboxylic acid] is a conformationally constrained analog of Trp and is more hydrophobic than Trp.…”