Publication Date: 2003
Daru Journal Of Pharmaceutical Sciences (15608115)(3)pp. 82-87
Majority of the currently available anticancer drugs are designed to have selective toxicity to rapidly dividing cells. Among these agents the focus of many studies are compounds obtained from natural products with high therapeutic index. In this study the cytotoxicity of HESA-A, a marine compound, on cancer and normal cells was evaluated. HESA-A was prepared in normal saline as a stock solution (0.8 mg/ml, pH=7.4), sterilized and further diluted to final concentrations of 0.4, 0.2, 0.1 and 0.05 mg/ml. Cells (MDA-MB-468, Hep-2, Hela as cancer cells; L929 and McCoy as normal cells) were grown in completed RPMI 1640 and seeded in 96 well micro plates at a concentration of 1-5 × 104 cells/ml. After incubation for 24 h, different concentrations of HESA-A were added and cells were further incubated for 72 h. Using MTT assay, percent cell survival was determined by ELISA at 540 nm. Doxorubicin was used as a positive control (20 μg /ml). HESA-A (0.4 mg/ml) reduced the number of viable MDA-MB-468 and Hela cells to less than 50%. For Hep-2 cells the IC 50 was 0.8 mg/ml. In normal cells IC50 could not be obtained at any given concentrations. These results suggest that HESA-A in therapeutic doses and in a concentration dependent manner inhibits the growth of cancer cells more selectively than normal cells.
Zarghi, A.,
Sadeghi, H.,
Fassihi, A.,
Faizi m., ,
Shafiee a., Publication Date: 2003
Farmaco (0014827X)(11)pp. 1077-1081
Alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-methylthio-1-phenylamino-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that in the series of alkyl esters increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units decreases activity. In the phenylalkyl ester series increasing the length of methylene chain also decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. In addition, two compounds, 5b and 5f were more active than the nifedipine. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
Publication Date: 2004
Farmaco (0014827X)(8)pp. 645-649
The antitumor activity of dihydroxyanthracenediones such as mitoxantrone on a panel of cancer cell lines during the last 30 years, led investigators to synthesize thousands of anthracycline analogs and test their cytotoxicity to identify compounds superior to the parent drugs in terms of increased therapeutic effectiveness, reduced toxicity or both. To achieve this, new synthesized congeners either have different side arms or have extra rings on their skeletons. Following these studies, we proposed total synthesis of 2-amino-N-[4-(2-amino-3-hydroxy-propionylamino)-9,10-dioxo-9, 10-dihydroanthracene-1-yl]-3-hydroxy-propionamide (V) and 6-amino-hexanoic acid [4-(5-amino-pentanoylamino)-9,10-dioxo-9,10-dihydro-anthracen-1-yl]-amide (VI). Acetylation of 1,4-diaminobenzene using acetyl chloride and reaction with phthalic anhydride under a Friedel-Crafts reaction and then cyclization gave 1, 4-diamino-anthraquinone. This compound was reacted with two amino acids (L-serine and 6-amino hexanoic acid) in their ester forms, using ethyl chloroformate as a coupling agent. Hydrolyzing esterified compounds gave their amino substituted derivatives. These compounds with diamine side arms are supposed to provide better intercalation with DNA. Synthesized novel ametantrone derivatives were tested against a panel of cancer cells (KB, Hela, MDA-MB-468 and K562), using MTT assay. The results showed that tested compounds inhibited the growth of cancer cells at micromolar concentrations. However, compound (VI) was more cytotoxic than compound (V) probably because of its longer side chains and better intercalation with DNA. © 2004 Elsevier SAS. All rights reserved.
Publication Date: 2004
Pharmaceutical Biology (13880209)(4-5)pp. 367-373
Breast cancer is the most prevalent type of cancer in pre- and postmenopausal women in most Western countries. In the treatment of metastatic breast cancer, doxorubicin has the broadest spectrum of antitumor activity of any drug currently available but produces a dose-dependent cardiomyopathy that limits its clinical usefulness. The aim of this research project was to target the affected tissues, which contain estrogen receptors (ERs). Initially, a series of estrogen derivatives with side chains linked at the 3- and 17-positions of estrone were synthesized, and then novel anticancer prodrugs were obtained from these by further linking these compounds to doxorubicin by means of various alkyl spacer groups. These estrogenic prodrugs were designed to target tumor cells containing ERs, found in human breast cancer cells, and to release the active anticancer moiety when internalized. The estrogenic prodrugs were then biologically evaluated using in vitro chemosensitivity assays against human ER-positive (MCF-7) and ER-negative (MCF-7ADR and MT-1) breast tumor cells and a leukemia (K562) cell line. The results showed that estrone derivatives with substituted aminoalcohol side chains of various lengths (2-6 carbons) linked to the 17-position of estrone were mostly inactive. Estronedoxorubicin prodrugs containing doxorubicin at the 3-position of estrone (CCRL 1042 and CCRL 1036) were relatively inactive and nonselective against all cell lines tested. However, when doxorubicin was linked to the 17-position of estrone, these prodrugs had at least an order greater activity than their 3-linked counterparts. Using a short aminoxyspacer group (2 carbons) at this position produced CCRL 1035, which had a lower activity against all cell lines tested compared to doxorubicin. In contrast, the prodrug incorporating doxorubicin at the 17-position of estrone via a long spacer group (12 carbons, CCRL 1033) was both potent and selective against ER-positive cells MCF-7. These studies have shown that linking doxorubicin to the 17-position of estrone via a long alkyl spacer group conferred selectivity of cytotoxic action against ER-positive breast cancer tumor cells.
