Biomedical subjects
Publications and source records attributed to Iwao Ojima.
[reaction: see text] A highly efficient short total synthesis of (+)-gamma-lycorane (>99% ee, 41% overall yield) was achieved by using the asymmetric allylic alkylation in the key step catalyzed by palladium complexes with novel chiral biphenol-based monodentate phosphoramidite ligands.
Screening of 120 taxanes identified a number of compounds that exhibited significant antituberculosis activity. Rational optimization of selected compounds led to the discovery that the C-seco-taxane-multidrug-resistance (MDR) reversal agents (C-seco-TRAs) are noncytotoxic at the upper limit of solubility and detection (>80 microM), while maintaining MIC(99) values of 1.25-2.5 microM against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis (MTB). Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation.
The reaction of dodec-11-ene-1,6-diynes or their heteroatom congeners with a hydrosilane catalyzed by Rh(acac)(CO)2 at ambient temperature and pressure of CO gives the corresponding fused 5-7-5 tricyclic products, 5-oxo-1,3a,4,5,7,9-hexahydro-3H-cyclopenta[e]azulenes or their heteroatom congeners, in excellent yields through a unique silicon-initiated cascade carbonylative carbotricyclization (CO-SiCaT) process. It has also been found that the 5-7-5 fused tricyclic products can be obtained from the same type of enediynes and CO through a novel intramolecular [2+2+2+1] cycloaddition process. The characteristics of these two tricyclization processes and the fundamental differences in their reaction mechanisms are discussed. This novel higher-order cycloaddition reaction has also been successfully applied to the tricyclization of undeca-5,10-diyn-1-als, affording the corresponding 5-7-5 fused-ring products bearing a seven-membered lactone moiety. Related [2+2+2] tricyclizations of enediyne and diynal substrates are also discussed. These newly discovered reactions can construct multiple bonds all at once, converting linear starting materials to polycyclic compounds in a single step. Thus, these new processes provide innovative routes to functionalized polycyclic compounds that are useful for the syntheses of natural and unnatural products.
Polyunsaturated fatty acids such as docosahexaenoic acid (DHA), linolenic acid, and linoleic acid were linked to the C-2' position of the second-generation taxoids that could overcome MDR caused by overexpressed ABC transporters. The new conjugates, tested in vivo, exhibited strong activity against drug-resistant colon cancer and drug-sensitive ovarian cancer xenografts in mice. Two of the new conjugates, DHA-SB-T-1214 and DHA-SB-T-1213, were found to achieve the total regression of drug-resistant and drug-sensitive tumors, respectively, in the animal models with substantially reduced systemic toxicity.
Traditional cancer chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be a killed by cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing severe undesirable side effects. Therefore, various drug delivery protocols and systems have been explored in the last three decades. Tumor cells overexpress many receptors and biomarkers, which can be used as targets to deliver cytotoxic agents into tumors. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate. The conjugate, which can be regarded as 'prodrug', should be systemically non-toxic. This means that the linker must be stable in circulation. Upon internalization into the cancer cell the conjugate should be readily cleaved to regenerate the active cytotoxic agent. Tumor-targeting conjugates bearing cytotoxic agents can be classified into several groups based on the type of cancer recognition moieties. This review describes recent advances in tumor-targeting drug conjugates including monoclonal antibodies, polyunsaturated fatty acids, folic acid, hyaluronic acid, and oligopeptides as tumor-targeting moieties.
The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.
A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure-activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.
A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.
A 95-fold epothilone B (EpoB)-resistant, but not dependent, A549 human lung carcinoma cell line, A549.EpoB40 (EpoB40), has a Gln to Glu mutation at residue 292 that is situated near the M-loop of betaI-tubulin. Further selection of this cell line with higher concentrations of EpoB produced A549.EpoB480 (EpoB480), which is approximately 900-fold resistant to EpoB. This cell line, like EpoB40, exhibits cross-resistance to Taxol and extreme sensitivity to vinblastine, but in contrast to EpoB40 it is unusually dependent on EpoB, requiring a minimum of 125 nmol/L EpoB to maintain normal growth. Sequence analysis of the beta-tubulin and Kalpha1-tubulin genes in EpoB480 showed that, in addition to the beta292 mutation, beta60 was mutated from Val to Phe and alpha195 was mutated from Leu to Met. Mass spectrometry indicated that both the Val(60)Phe and Leu(195)Met mutations in betaI- and Kalpha1-tubulin, respectively, were expressed at the protein level. Molecular modeling indicated that beta60 is located at the end of the H1-S2 loop that has been implicated as a principal partner of the M-loop for contacts between protofilaments. A mutation at beta60 could inhibit the lateral contacts between protofilaments, thereby destabilizing microtubules. alpha195 is located at the external surface of the microtubule that has been proposed as the domain that interacts with a variety of endogenous proteins, such as stathmin and microtubule-associated protein 4. A mutation at alpha195 could modulate the interactions between tubulin and regulatory proteins. We propose that the betaVal(60)Phe mutation plays a critical role in the drug-dependent phenotype of EpoB480 cells.
Antibody-based delivery of cytotoxic agents, including toxins, to tumours can dramatically reduce systemic toxicity and increase therapeutic efficacy. The advantage of a monoclonal antibody (mAb) is superior selectivity towards antigens expressed on the surface of cancer cells. Recent advances in biotechnology accelerated progress in the pharmaceutical applications of mAbs. A cytotoxic warhead is attached to a mAb in an immunoconjugate via a linker, which is stable in circulation but efficiently cleaved in the tumour tissue. The warhead, mAb and linker play important roles in the successful design of potent and efficient immunoconjugates. To date, one mAb-cytotoxic agent conjugate has been approved by the FDA and several other candidates are in various stages of clinical trials. This review describes the recent progress in the design and development of mAb-based immunoconjugates of cytotoxic agents, and summarises the criteria for the critical choices of a suitable mAb, linker and cytotoxic agent to design an efficacious immunoconjugate.
[reaction: see text] The first Rh-catalyzed intramolecular [2 + 2 + 2 + 1] cycloaddition reaction of enediynes and CO is reported. This novel higher order cycloaddition process gives the corresponding 5-7-5 ring systems in high yield and selectivity. This process is another significant addition to the arsenal of cycloaddition-based synthetic methods, which provide powerful tools for rapid and efficient construction of complex polycyclic systems.
Copper-catalyzed asymmetric conjugate addition of diethylzinc to nitroalkenes using new chiral monodentate phosphoramidite ligands proceeds with high enantioselectivity up to 99% ee. [reaction: see text]
The targeted delivery of taxoids, in the form of taxane-antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing linker at various positions of the taxoid framework have been prepared to investigate the most suitable position for conjugation. A second series of taxoids modified at the C-2 position aimed at increasing the potency of these taxanes has also been prepared.
Based on a common pharmacophore model and the hypothesis that the baccatin core of taxoids is a scaffold securing the proper orientation of the side chains, a bicyclic alkaloid scaffold was designed as a baccatin surrogate. Using this scaffold, two novel macrocyclic and open-chain 'taxoid-mimicking' compounds were synthesized. Two of these 'taxoid-mimics', 2 and 3, were found to possess cytotoxicity with micromolar level IC50 values against human breast cancer cell lines.
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Monodentate phosphoramidite ligands have been developed based on enantiopure 6,6'-dimethylbiphenols with axial chirality. These chiral ligands are easy to prepare and flexible for modifications. The fine-tuning capability of these ligands plays a significant role in achieving high enantioselectivity in the asymmetric hydroformylation of allyl cyanide and the conjugate addition of diethylzinc to cycloalkenones.
PURPOSE: The taxanes paclitaxel and docetaxel are substrates for P-glycoprotein (Pgp), an ATP-binding cassette (ABC) transport protein associated with multidrug resistance (MDR). In contrast, the synthetic taxane ortataxel (BAY 59-8862, IDN-5109) is effective against Pgp-expressing cells by virtue of modulation of Pgp-mediated transport. The synthetic taxane tRA96023 also modulates Pgp and is noncytotoxic due to removal of the tubulin-binding side chain at the C-13 position of the taxane backbone. We studied the effects of ortataxel and tRA96023 on the other MDR-associated ABC transport proteins, multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP, MXR, ABCG2). METHODS: Modulation of mitoxantrone, daunorubicin and doxorubicin retention and cytotoxicity by ortataxel and tRA96023 was studied in established cell lines overexpressing Pgp, MRP-1 and wild type (BCRP(R482)) and mutant (BCRP(R482T)) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively. RESULTS: Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRP(R482), in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRP(R482) and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRP(R482T). CONCLUSIONS: The synthetic taxane derivatives ortataxel and tRA96023 are broad-spectrum ABC protein modulators. Further studies will seek to identify a noncytotoxic synthetic taxane that modulates Pgp, MRP-1 and BCRP.
[reaction: see text] New monodentate phosphite ligands have been developed from axially chiral biphenols, which show excellent enantioselectivity in the Rh(I)-catalyzed hydrogenation of dimethyl itaconate. The new chiral ligand system is suitable to create libraries and possesses fine-tuning capability.