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Combretastatin A4-?-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy.

ABSTRACT: Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two ?-galactose-conjugated CA4s (CA4-?Gals), CA4-?Gal-1 and CA4-?Gal-2. CA4 was liberated from CA4-?Gals by ?-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-?Gal-2, which has a self-immolative benzyl linker between CA4 and the ?-galactose moiety, was more cytotoxic to ovarian cancer cell lines than CA4-?Gal-1 without a linker. Therefore, CA4-?Gal-2 can serve as a platform for the design and manufacture of prodrugs for ovarian cancer PMT.

SUBMITTER: Doura T

PROVIDER: S-EPMC5304305 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy.

Doura Tomohiro T Takahashi Kazuaki K Ogra Yasumitsu Y Suzuki Noriyuki N

ACS medicinal chemistry letters 20170120 2

Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytot ...[more]

PMID: 28197314

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Project description:Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50=0.11-40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50=0.62-1.5μM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0μM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.

Dataset Information

Combretastatin A4-?-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy.

Publications

Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy.

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