Derivatives of a Novel Cyclopeptolide. 2. Synthesis, Activity against Multidrug Resistance in CHO and KB Cells in vitro, and Structure-Activity Relationships
Abstract:A series of derivatives of the novel cyclopeptolide 1 was prepared, and their ability to chemosensitize multi drug resistant CHO and KB cells in vitro was evaluated. In contrast to the parent compound, several of the derivatives were found to be highly active. In particular, conversion of the R-lactic acid residue of 1 into its S-isomer via lactone ring cleavage and recyclization with inversion resulted in a marked enhancement of activity. Some of these derivatives (e.g., 15a, SDZ 280.446) belong to the most p… Show more
“…All values (other than IC 50 s) are normalized to those for CsA. The structures of dihydroCsA, PSC-833, and cyclosporin H have been reported previously (17,31,51).…”
The immunosuppressive agent cyclosporin A (CsA) also possesses broad-spectrum antimicrobial activity. Previous investigators have reported that the obligate intracellular protozoan Toxoplasma gondii is sensitive to CsA. We have measured the sensitivity of Toxoplasma to 26 CsA derivatives that maintain only a subset of the parent compound's activity. We identified one compound, SDZ 215-918, that is a particularly potent inhibitor of parasite invasion and replication, with a 50% inhibitory concentration of 0.45 microg/ml, which is 10-fold lower than that of CsA. Kinetic studies demonstrate that activity has a rapid onset (half-life, < or = 20 min) and is initially reversible, although long-term exposure (> 24 h) to 5 microg/ml is lethal; in contrast, this concentration had no effect on host cell protein synthesis or cell division. SDZ 215-918 acts directly on the parasite, as demonstrated by inhibition of macromolecular synthesis in host-free extracellular parasites. Inhibition of invasion is due to a reduction in parasite motility. SDZ 215-918 does not bind to cyclophilins, the ubiquitous cyclosporin-binding proteins, but is a potent inhibitor of the mammalian P glycoprotein, a member of the ATP binding cassette transporter superfamily and the pump responsible for multidrug resistance in cancer and parasite cell lines. SDZ 215-918 blocks the efflux of rhodamine 123 from extracellular parasites, consistent with inhibition of a P glycoprotein-like pump. We suggest that a P glycoprotein or a related transporter plays a crucial role in the biology of Toxoplasma and may be a novel target for antiparasitic compounds. Preliminary studies with animals indicate that SDZ 215-918 inhibits parasite growth in vivo; its relationship to CsA may make it suitable for clinical development.
“…All values (other than IC 50 s) are normalized to those for CsA. The structures of dihydroCsA, PSC-833, and cyclosporin H have been reported previously (17,31,51).…”
The immunosuppressive agent cyclosporin A (CsA) also possesses broad-spectrum antimicrobial activity. Previous investigators have reported that the obligate intracellular protozoan Toxoplasma gondii is sensitive to CsA. We have measured the sensitivity of Toxoplasma to 26 CsA derivatives that maintain only a subset of the parent compound's activity. We identified one compound, SDZ 215-918, that is a particularly potent inhibitor of parasite invasion and replication, with a 50% inhibitory concentration of 0.45 microg/ml, which is 10-fold lower than that of CsA. Kinetic studies demonstrate that activity has a rapid onset (half-life, < or = 20 min) and is initially reversible, although long-term exposure (> 24 h) to 5 microg/ml is lethal; in contrast, this concentration had no effect on host cell protein synthesis or cell division. SDZ 215-918 acts directly on the parasite, as demonstrated by inhibition of macromolecular synthesis in host-free extracellular parasites. Inhibition of invasion is due to a reduction in parasite motility. SDZ 215-918 does not bind to cyclophilins, the ubiquitous cyclosporin-binding proteins, but is a potent inhibitor of the mammalian P glycoprotein, a member of the ATP binding cassette transporter superfamily and the pump responsible for multidrug resistance in cancer and parasite cell lines. SDZ 215-918 blocks the efflux of rhodamine 123 from extracellular parasites, consistent with inhibition of a P glycoprotein-like pump. We suggest that a P glycoprotein or a related transporter plays a crucial role in the biology of Toxoplasma and may be a novel target for antiparasitic compounds. Preliminary studies with animals indicate that SDZ 215-918 inhibits parasite growth in vivo; its relationship to CsA may make it suitable for clinical development.
“…This reaction has been used in a number of 11- to 16-membered macrolactones, ,,− in the total syntheses of natural products such as (+)-amphidinolide K (eq a in Scheme ), 19-epi-avermectin B 1 , (+)-brefeldin C, citreofuran, antibiotics derived from erythromycin, , (+)-gloeosporone, − hypothemycin, cyclothialidine, lasiodiplodin, lobotamide C, ,, latrunculins A and B, − laulimalide, − where Yamaguchi and Keck methodologies result in Z / E isomerization of the conjugated double bond (eq b in Scheme ), leucascandrolide A, − (+)-milbemycin β 3 , , (+)-patulolide, suspensolide, , diolides UK-2A and UK-3A, , verrucarin A, zearalane, and aplyronine A analogues, in the total synthesis of griseoviridin, and in several approaches to its thiolactone core, − where, in particular, a highly strained nine-membered lactone has been obtained by Pancrazi 588 (see eq c in Scheme ). This methodology has also been successfully used in the syntheses of various cyclodepsipeptides as illustrated in Scheme . ,,− 69 …”
Section: Macrolactonizations By “Alcohol” Activationmentioning
“…Emmer et al, (53), by expert observation 70 triazines DC-3F/AD KB-A1 P388/VCR Adriamycin, vincristine A two monoalkylamino substited triazine core rather than a pyrimidine one at the left; a sec-amino substituted piperidine core rather than a piperazine one in the middle; the right part can be either a substituted benzhydryl or dibenzosuberane-like (more active) group, the nature of the bridge also affected activity; the spacer length between the left and right parts was most sensitive to activity, longer spacer may lead to completely inactive.…”
Multidrug resistance (MDR) is one of the major obstacles to long term successful cancer chemotherapy. The use of MDR reversal (MDRR) agents is a promising approach to overcome the undesired MDR phenotype. To design more effective MDRR agents that are urgently needed for clinical use, a data set of 609 diverse compounds tested for MDRR activity against P388/ADR-resistant cell lines was submitted to the MULTICASE computer program for structure-activity analysis. Some substructural features related to MDRR activity were identified. For example, the CH2-CH2-N-CH2-CH2 group was found in most of the active compounds, and the activity was further enhanced by the presence of (di)methoxylphenyl groups, whereas the presence of a stable quaternary ammonium salt, a carboxylic, a phenol, or an aniline group was found to be detrimental to activity. Possible explanations for these observations are proposed. Some physicochemical properties, e.g., the partition coefficient (log P) and the graph index (which in some sense measures the "complexity" of a molecule) were also found to be relevant to activity. Their role in MDRR was also rationalized. Based on our quantitative structure-activity relationship study of MDRR agents, some compounds with desired substructural features and activity were identified from the MACCS-II and National Cancer Institute DIS databases and tested experimentally. Our study may also help the rational design of anti-cancer drugs. Based on this study and on observations by other researchers, we postulate that P-glycoprotein-mediated resistance to paclitaxel could probably be eliminated by proper substitution of its benzamido and phenyl groups. Several novel compounds with the paclitaxel skeleton are proposed, which may lead to a new generation of paclitaxel anti-cancer drugs with less MDR potential.
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