ABSTRACT
(-)-Homo-renieramycin G and its twenty derivatives were prepared from l-tyrosine methyl ester via a multi-step route. Their cytotoxicities were tested against four human cancer cell lines (A549, HeLa, KB and BGC-823). (-)-Renieramycin G and (-)-homo-renieramycin G showed comparable cytotoxicity against these four cancer cell lines, which indicated that the expansion of ring C from the six-membered 1,4-piperazinone to the seven-membered 1,4-diazepanone had no obvious impact on the cytotoxicity. Compound 42 with methyl side chain and compounds 38-41 with heterocyclic aromatic side chains at C-23 exhibited the most potent cytotoxicity with the IC50 values at the level of 10-6 M.
ABSTRACT
Two series of novel hexacyclic skeletons and their thirty-four derivatives were prepared from l-tryptophan and l-DOPA. The cytotoxicities of these compounds were tested against four human cancer cell lines HCT-116, HepG2, BGC-823 and A2780. Compounds with the tetrahydro-ß-carboline moiety in the left-half of the hexacyclic skeleton showed more potent cytotoxicity with IC50 values in the range of 10-7-10-9 M. Compound 20 with the 4-methoxybenzamide side chain showed potent cytotoxicity towards HepG2 with an IC50 value of 1.32 nM. Compounds 29 and 30 with 2-pyridine amide and (2E)-3-(3-thifluoromethyl-phenyl)acrylic amide side chains showed selective cytotoxicity towards A2780 with IC50 values of 1.73 nM and 7 nM, respectively.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cytotoxins/chemical synthesis , Drug Design , Levodopa/chemistry , Tryptophan/chemistry , Antibiotics, Antineoplastic/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cytotoxins/pharmacology , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Isoquinolines/chemistry , Structure-Activity RelationshipABSTRACT
(-)-Saframycin A and its nineteen analogues were prepared from L-tyrosine in 24 steps, and their structures were confirmed through NMR and HRMS. The cytotoxicities of these compounds were tested against HCT-8, BEL-7402, Ketr3, A2780, MCF-7, A549, BGC-803, Hela, HELF and KB cell lines. The IC(50) values of the cytotoxicity of most compounds were at the level of nM. Compound 7d with 2-furan amide side chain showed the most potent cytotoxicity of all these compounds with an average IC(50) value of 6.06 nM.
Subject(s)
Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Isoquinolines/pharmacology , Neoplasms/drug therapy , Streptomyces/chemistryABSTRACT
The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Tyrosine/chemistry , Antibiotics, Antineoplastic/chemistry , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Molecular Conformation , StereoisomerismABSTRACT
(-)-Renieramycin G and fifteen C-22 analogs were prepared employing l-tyrosine as the chiral starting material. These analogs, along with (-)-renieramycin G itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, A2780, MCF-7, A549, BGC-823, Ketr3, KB, Hela cells. The IC(50) values of most of these analogs were at the level of µM. Among these analogs, 2-thiophenecarboxylate ester derivative 17 exhibited potent cytotoxic activity against KB cell line with the IC(50) of 20 nM. From this study, it could be concluded that the C-22 side chain played an important role in the cytotoxic potency and specificity of this class of (-)-renieramycin G derivatives.