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To achieve efficient and reliable heating in severe cold regions below −20 °C, this paper investigates a R134a/CO2 cascade air source heat pump system (ASHP). Firstly, a simulation model is constructed and used for energy performance analysis. Then experiments are carried out for model verification and performance investigation. Finally, its performance is evaluated in detail with the meteorological data of Harbin under different working conditions for energy performance forecast. Simulation results shows the heating coefficient of performance (COP) increases with higher ambient temperature and lower water supply temperature. At the same time, the modeling errors on coefficient of performance (COP) are all within ±0.2%. The experimental results show that the proposed R134a/CO2 ASHP can supply water above 50 °C with high COP up to 3.07 and 1.60 when the ambient air temperature is −5 °C and −45 °C, respectively. Furthermore, under four working conditions, the heating seasonal performance factors (HSPF) are all above 2.30 and the best is 2.39 for the −25 °C nominal operating temperature and the typical working condition of civil buildings (15 °C). Both the experimental data and the simulation results show that the proposed R134a/CO2 cascade air source heat pump system can provide efficient and reliable heating in severe cold regions.

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.

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 IC 50 values against human breast cancer cell lines.

[reaction: see text] The first total synthesis of resorcinylic macrolide aigialomycin D was described. The resorcinylic moiety was constructed by a highly efficient Diels-Alder reaction using a disiloxydiene and a 14-membered "ynolide" as the dienophile synthesized by ring-forming olefin metathesis.

Molecular chaperone Hsp90 has emerged as one of the most exciting new targets for anticancer therapy. Natural product-based modulators, such as radicicol (1), inhibit Hsp90 and induce the breakdown of its client proteins,thereby blocking multiple critical oncogenic pathways. Several total synthesis endeavors directed toward radicicol have been accomplished. Cycloproparadicicol (2), a potent Hsp90 inhibitor and highly promising pre-clinical anticancer agent, was discovered through a convergent total synthesis approach. In an effort to devise a more efficient and concise route to reach 2, a novel 'ynolide' protocol, featuring an ynolide-bissiloxydiene Diels-Alder addition, was designed and reduced to practice. This methodology was also extended to aigialomycin D.

[reaction: see text] Novel C2-C3'N-linked macrocyclic taxoids are synthesized using intramolecular Heck reaction in the key step. Macrocyclization proceeds with high regioselectivity in good yield. Taxoids bearing an olefin moiety at C2 and an iodide at C3'N give exo-products exclusively. However, the endo-products are formed with up to 100% regioselectivity just by switching the positions of the olefin and the iodide moieties. Some of these macrocyclic taxoids are significantly cytotoxic.

The xanthophylls—lutein, zeaxanthin, and meso-zeaxanthin (L&Z)—are found in the central region of the primate retina, which is called the macula lutea (yellow spot). How they are anchored there and what their function is has been debated for over 50 years. Here, we present evidence that they may be bound to the paclitaxel (Taxol) binding site of the β-tubulin subunit of microtubules and that a major function may be to modulate the dynamic instability of microtubules in the macula. Also, we compare nucleic acid and amino acid sequences of tubulins that are in human brain with those we have isolated from human-retina and monkey-macula cDNA libraries. In so doing, we suggest that in primates, class I β-tubulin consists of at least two subtypes (βIa and βIb). Alignment analysis of the sequences of the genes for βIa and βIb indicates that the corresponding mRNAs may have other functions in addition to that of coding for proteins. Furthermore, we show that there are at least five different types of β-tubulin in the macula lutea of rhesus monkey.

A series of novel macrocyclic taxoids 6 and 6‘ bearing 16-, 17-, and 18-membered rings connecting the substituents at the C-2 and C-3‘ positions were designed and synthesized. The syntheses of these macrocycles 6 and 6‘ were accomplished using the highly efficient ruthenium-catalyzed ring-closing metathesis (RCM) of taxoid-ω,ω‘-dienes 7 in the key step. Taxoid-ω,ω‘-dienes 7 were obtained through the ring-opening coupling of 4-alkenyl-β-lactams 9 with 2-alkenoylbaccatins 8 in good to high yields. Although various novel pentacyclic macrocycles 6 and 6‘ were successfully synthesized, there were cases in which the desired RCM did not proceed. The scope and limitation of RCM in its application to highly functionalized complex substrates are discussed. All macrocyclic taxoids 6 and 6‘ were found to be cytotoxic, with some of them exhibiting submicromolar IC50 values against a human breast cancer cell line.

A series of highly potent second-generation taxoids bearing a 2-methylprop-1-enyl or a 2-methylpropyl group at C-3′ with modifications at the C-2, C-10, and C-14 positions was synthesized through the coupling of racemic cis-β-lactams with properly protected/modified baccatin and 14-OH-baccatin. A high level of kinetic resolution was observed for all cases examined. The observed highly efficient enantiomer differentiation is ascribed to the markedly different chiral environment between the (+)- and (−)-β-lactams in their approach to the chiral framework of the enantiopure lithium alkoxide of a baccatin in the ring-opening coupling process. It was also observed that substantially higher selectivity was achieved when 14-OH-baccatin-1,14-carbonate was used. Analysis of the transition state models revealed that the repulsive interactions between the 3-TIPS group of a (−)-β-lactam with 1,14-carbonate group of the baccatin substantially increases the asymmetric bias in the kinetic resolution process, favoring the reaction of a (+)-β-lactam, which leads to the observed excellent selectivity. Chirality 12:431–441, 2000. © 2000 Wiley-Liss, Inc.

A series of second-generation taxoids bearing a substitutent on the C-2-benzoyl group and modifications at C-3′/C-10 positions was synthesized. These taxoids exhibited 2–3 orders of magnitude higher potency than that of paclitaxel against drug-resistant human breast cancer cell lines. It is also noteworthy that three taxoids showed almost no difference in activity against drug-resistant and drug-sensitive cell lines, which are categorized as “advanced second generation taxoids“.

A series of novel macrocyclic taxoids was designed and synthesized by connecting the C-2 and C-3′ N positions of the taxoid framework with various tethers. Cytotoxicity of these macrocyclic taxoids was evaluated against a human breast cancer cell line LCC6-WT, and a couple of the taxoids exhibited 0.09–0.3 μM IC 50 values.

Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C3'BzN), which are ca. 7.5 A apart, with a short linker (4-6 atoms). 7-TES-14beta-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-beta-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.

Di- and trivalent glycopeptide mimics of the HIV 2G12 epitope have been synthesized and evaluated for their comparative 2G12 binding characteristics. The epitope mimics consist of a cyclic peptide scaffold (unrelated to gp120 peptide sequences) attached via aspartate linkages to two or three copies of the high-mannose glycan, Man9GlcNAc2. The synthesis has been achieved via high-yielding double and triple Lansbury aspartylations of Man9GlcNAc2-NH2 with peptides containing, respectively, two and three aspartate residues. Conjugation of such constructs with an immunogenic carrier protein, OMPC, has been accomplished through the peptide's cysteine sulfhydryl function, and Biacore assays have shown that binding affinity for 2G12 increases with increasing valency.

This review provides an overview of our explorations into oligosaccharide and glycoconjugate construction for the creation and evaluation of glycopeptide-based vaccines. The basis for these investigations is the known tendency of both cancer cells and viruses to express selective carbohydrate motifs in the form of glycoproteins or glycolipids. Utilization of these carbohydrates in a glycopeptide-based vaccine could potentially trigger immune recognition, generating a protective response against the disease. However, obtaining large quantities of such compounds from natural sources is extremely difficult. Over the past two decades, our lab has been engaged in the total synthesis of complex oligosaccharides and glycoconjugates. With this knowledge and experience, we have begun to evaluate, in many cases at the clinical level, whether the human immune system is capable of mounting a response against such fully synthetic carbohydrate antigens in a focused and useful way. Toward this goal, we have merged the powers of both chemistry and immunology to provide insight into this problem. The synthesis and evaluation of potential vaccines for both cancer and HIV will be described.

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitors targeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to their ability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselves with a vastly important total synthesis of such an inhibitor. We accomplished this via a new approach, which we term the “ynolide method”, directed to the synthesis of resorcinylic macrolides, including cycloproparadicicol and aigialomycin D. The key features of the syntheses involve cobalt-complexation-promoted ring-closing metathesis (RCM) to generate ynolides, followed by Diels−Alder reaction with dimedone-derived bis-siloxy dienes to elaborate the benzo system. A number of interesting analogues were synthesized using this protocol. They were evaluated for their inhibitory activity against the growth of breast cancer cell line, MCF-7. The potency of their cytotoxicity was found to be consis...

Synthetic gp120331-335 glycopeptide fragments carrying hybrid and high-mannose type N-linked glycans were evaluated for binding to broadly neutralizing antibody 2G12 using surface plasmon resonance technology. None of the hybrid-type constructs demonstrated binding to 2G12. In the high-mannose series, the “Cys dimer” construct, presenting two undecasaccharide glycans, showed significantly higher binding than the Cys-protected monomer. The binding of the dimeric structure was further investigated in competition with recombinant gp120. The data suggest that gp120 and its designed synthetic epitope construct bind to the same site on 2G12.

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitors targeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to their ability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselves with a vastly important total synthesis of such an inhibitor. We accomplished this via a new approach, which we term the "ynolide method", directed to the synthesis of resorcinylic macrolides, including cycloproparadicicol and aigialomycin D. The key features of the syntheses involve cobalt-complexation-promoted ring-closing metathesis (RCM) to generate ynolides, followed by Diels-Alder reaction with dimedone-derived bis-siloxy dienes to elaborate the benzo system. A number of interesting analogues were synthesized using this protocol. They were evaluated for their inhibitory activity against the growth of breast cancer cell line, MCF-7. The potency of their cytotoxicity was found to be consistent with their ability to degrade the oncogenic protein, Her2. From these assays, cycloproparadicicol was identified as a most promising candidate for further development.

The first total synthesis of resorcinylic macrolide aigialomycin D was described. The resorcinylic moiety was constructed by a highly efficient Diels−Alder reaction using a disiloxydiene and a 14-membered “ynolide” as the dienophile synthesized by ring-forming olefin metathesis.

Taxoids bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody immunoconjugates were designed, synthesized and their activities evaluated. A highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in severe combined immune deficiency mice, resulting in complete inhibition of tumor growth in all the treated mice.

A series of novel macrocyclic taxoids was designed and synthesized by connecting the C-2 and C-3′ N positions of the taxoid framework with various tethers. Cytotoxicity of these macrocyclic taxoids was evaluated against a human breast cancer cell line LCC6-WT, and a couple of the taxoids exhibited 0.09–0.3 μM IC 50 values.