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1.
Hypoxia (Auckl) ; 5: 45-59, 2017.
Article in English | MEDLINE | ID: mdl-28580362

ABSTRACT

PURPOSE: There is an urgent need to develop effective therapies and treatment strategies to treat hypoxic tumors, which have a very poor prognosis and do not respond well to existing therapies. METHODS: A novel hypoxia-targeting agent, KEMTUB012-NI2, was synthesized by conjugating a 2-nitroimidazole hypoxia-targeting moiety to a synthetic tubulysin, a very potent antimitotic. Its hypoxic selectivity and mode of action were studied in breast cancer cell lines. RESULTS: KEMTUB012-NI2 exhibited a similar selectivity for hypoxic cells to that of tirapazamine, a well-established hypoxia-targeting agent, but was >1,000 times more potent in cell cytotoxicity assays. The hypoxia-targeting mechanism for both KEMTUB012-NI2 and tirapazamine was selective and mediated by one-electron reductases. However, while cytochrome p450 reductase (POR) downregulation could inhibit tirapazamine cytotoxicity, it actually sensitized hypoxic cells to KEMTUB012-NI2. CONCLUSION: KEMTUB012-NI2 is a potent new agent that can selectively target hypoxic cancer cells. The hypoxia selectivity of KEMTUB012-NI2 and tirapazamine appears to be differentially activated by reductases. Since reductases are heterogeneously expressed in tumors, the different activation mechanisms will allow these agents to complement each other. Combining POR downregulation with KEMTUB012-NI2 treatment could be a new treatment strategy that maximizes efficacy toward hypoxic tumor cells while limiting systemic toxicity.

2.
Chemistry ; 23(24): 5842-5850, 2017 Apr 27.
Article in English | MEDLINE | ID: mdl-28300330

ABSTRACT

Synthetic tubulysins 24 a-m, containing non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multistep synthesis. A key step was the formation of differently N-substituted Ile-Tuv fragments 10 by using an aza-Michael reaction of azido-Ile derivatives 8 with the α,ß-unsaturated oxo-thiazole 5. A structure-activity relationship study using a panel of human tumour cell lines showed strong anti-proliferative activity for all compounds 24 a-m, with IC50 values in the sub-nanomolar range, which were distinctly lower than those of tubulysin A, vinorelbine and paclitaxel. Furthermore, 24 a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumour cell lines with acquired resistance to doxorubicin. Compounds 24 e and 24 g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24 e and 24 g interfere with tubulin polymerization in a vinca alkaloid-like manner and prevent paclitaxel-induced assembly of tubulin polymers. Both compounds exerted antimitotic activity and induced apoptosis in cancer cells at very low concentrations. Compound 24 e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, the growth of which was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.


Subject(s)
Antineoplastic Agents/chemical synthesis , Tubulin Modulators/chemical synthesis , Tubulin/metabolism , Valine/analogs & derivatives , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HT29 Cells , Humans , Mice , Microscopy, Fluorescence , Neoplasms/drug therapy , Neoplasms/pathology , Paclitaxel/toxicity , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin/chemistry , Tubulin Modulators/therapeutic use , Tubulin Modulators/toxicity , Valine/chemistry , Vinblastine/analogs & derivatives , Vinblastine/therapeutic use , Vinblastine/toxicity , Vinorelbine
3.
Cancer Res ; 74(20): 5700-10, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25145670

ABSTRACT

Tubulysins are highly toxic tubulin-targeting agents with a narrow therapeutic window that are interesting for application in antibody-drug conjugates (ADC). For full control over drug-antibody ratio (DAR) and the effect thereof on pharmacokinetics and tumor targeting, a dual-labeling approach was developed, wherein the drug, tubulysin variants, and the antibody, the anti-HER2 monoclonal antibody (mAb) trastuzumab, are radiolabeled. (131)I-radioiodination of two synthetic tubulysin A analogues, the less potent TUB-OH (IC50 > 100 nmol/L) and the potent TUB-OMOM (IC50, ~1 nmol/L), and their direct covalent conjugation to (89)Zr-trastuzumab were established. Radioiodination of tubulysins was 92% to 98% efficient and conversion to N-hydroxysuccinimide (NHS) esters more than 99%; esters were isolated in an overall yield of 68% ± 5% with radiochemical purity of more than 99.5%. Conjugation of (131)I-tubulysin-NHS esters to (89)Zr-trastuzumab was 45% to 55% efficient, resulting in ADCs with 96% to 98% radiochemical purity after size-exclusion chromatography. ADCs were evaluated for their tumor-targeting potential and antitumor effects in nude mice with tumors that were sensitive or resistant to trastuzumab, using ado-trastuzumab emtansine as a reference. ADCs appeared stable in vivo. An average DAR of 2 and 4 conferred pharmacokinetics and tumor-targeting behavior similar to parental trastuzumab. Efficacy studies using single-dose TUB-OMOM-trastuzumab (DAR 4) showed dose-dependent antitumor effects, including complete tumor eradications in trastuzumab-sensitive tumors in vivo. TUB-OMOM-trastuzumab (60 mg/kg) displayed efficacy similar to ado-trastuzumab emtansine (15 mg/kg) yet more effective than trastuzumab. Our findings illustrate the potential of synthetic tubulysins in ADCs for cancer treatment.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Animals , Antibodies, Monoclonal, Humanized/chemistry , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Drug Stability , Female , Humans , Maximum Tolerated Dose , Mice, Nude , Oligopeptides , Tissue Distribution , Trastuzumab , Xenograft Model Antitumor Assays
4.
Org Biomol Chem ; 10(26): 5045-8, 2012 Jul 14.
Article in English | MEDLINE | ID: mdl-22618598

ABSTRACT

N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This desymmetrization process provides highly functionalized cyclobutanones with control over three contiguous stereogenic centers.

5.
Org Biomol Chem ; 9(21): 7517-24, 2011 Nov 07.
Article in English | MEDLINE | ID: mdl-21938296

ABSTRACT

The Kulinkovich-de Meijere reaction between an unsaturated Grignard reagent and a chiral amide takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans cyclopropylamines. These compounds are transformed in four steps into the corresponding N-protected ß,γ-methano-GABA derivatives, which are obtained for the first time in enantiomerically pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.


Subject(s)
Cyclopropanes/chemical synthesis , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/chemical synthesis , Crystallography, X-Ray , Cyclopropanes/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , gamma-Aminobutyric Acid/chemistry
6.
Org Biomol Chem ; 7(17): 3512-9, 2009 Sep 07.
Article in English | MEDLINE | ID: mdl-19675908

ABSTRACT

The high versatility of 1-phenylsulfenyl- or 1-phenylsulfonyl-cyclopropylketones has been exploited for the regioselective synthesis of trans-2,3-disubstituted cyclobutanones, 2,4,5-trisubstituted 3,6-dihydro-2H-pyrans and cis-2-alkyl- or cis-2-aryl-cyclopropylphenylsulfones.

7.
Chem Senses ; 32(8): 755-63, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17630413

ABSTRACT

A number of oxaspiropentane derivatives (OXPs) were tested as potential (+)-disparlure analogues, with the aim of identifying any possible interaction of these compounds, be it additive, synergetic, or inhibitory, with the pheromone response in the male gypsy moth Lymantria dispar. As assessed by male electroantennograms, 2 OXPs, 2-decyl-1-oxaspiro[2.2]pentane (OXP-01) and 4-(1-oxaspiro[2.2]pent-2-yl)butan-1-ol (OXP-04), were found to be effective. OXP-01 had no stimulatory effect but strongly decreased the response to (+)-disparlure in a blend in a 1:1 ratio. By contrast, OXP-04 proved to be more stimulating than (+)-disparlure and also had an additive effect in the blend. Single-cell recordings from the sensilla trichoidea showed the activity of 2 cells, one of which responded to (+)-disparlure. OXP-01 reduced the stimulating effectiveness of pheromone by silencing the pheromone-responding unit when the 2 compounds were presented in blend, whereas OXP-04 mimicked the pheromone response, evidenced by exciting the pheromone-responding neuron when tested alone. Behavioral observations are in agreement with electrophysiological results.


Subject(s)
Electrophysiology/methods , Epoxy Compounds/chemistry , Sex Attractants/metabolism , Spiro Compounds/chemistry , Air , Animals , Behavior, Animal , Dose-Response Relationship, Drug , Female , Male , Models, Chemical , Moths , Odorants , Pheromones , Sexual Behavior, Animal , Time Factors
8.
Org Lett ; 9(3): 541-4, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17249807

ABSTRACT

[reaction: see text] Acid-catalyzed ring expansion of chiral cyclopropyl and cyclobutyl derivatives for the synthesis of carbo- and heterocyclic compounds is reported. The starting materials have been successfully prepared by l-proline-catalyzed direct asymmetric aldol reactions of 1-phenylthiocycloalkyl carboxaldehydes with ketones.

9.
Org Lett ; 7(21): 4565-8, 2005 Oct 13.
Article in English | MEDLINE | ID: mdl-16209480

ABSTRACT

[reactions: see text] Regioselective synthesis of 2,4,5- or 3,4,5-trisubstituted 2,3-dihydrofurans has been realized by using donor-acceptor cyclopropanes or by a Corey ylide reaction with alpha-sulfenyl-, alpha-sulfinyl-, or alpha-sulfonylenones. The method allowed a straightforward synthesis of the natural product calyxolane B.


Subject(s)
Cyclopropanes/chemistry , Furans/chemical synthesis , Sulfur Compounds/chemistry , Furans/chemistry , Molecular Structure , Oxidation-Reduction , Stereoisomerism
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