A possible correlation between antioxidant and antidiabetic potentials of oxovanadium(IV) complexes

Diabetes mellitus is one of the metabolic disorders resulting from excess production of reactive oxygen species (ROS) over the normal level and also due to dysfunction in the antioxidant defense mechanism, possibly both occurring simultaneously. Excess ROS are normally scavenged by antioxidants. Transition metal complexes exhibit such antioxidant property by scavenging the excess free radicals (one type of ROS) in such disorders. In this study, we report on synthesis, characterization, and in vitro study on antioxidant property of a few new ester-based vanadium(IV) complexes, namely, bis(1,1-dimethylethylpropanedioato)oxovanadium(IV)—[VO(DTBM)₂]; bis(methyl-3-oxopentanoato)oxovanadium(IV)—[VO(MPA)₂]; bis(ethyl-3-oxopentanoato)oxovanadium(IV)—[VO(EPA)₂]; bis(2-methyl-1,3-dimethylpropanedioato)oxovanadium(IV)—[VO(DMMM)₂] and bis(2-bromo-1,3-diethylpropanedioato)oxovanadium(IV)—[VO(BDEM)₂], and also furan-based vanadium complexes. Antidiabetic potential of selected complexes has been estimated. An attempt has also been made to correlate antioxidant and antidiabetic potentials of selected complexes. Our study reveals that compounds exhibiting higher glucose lowering effect seem to possess good antioxidant potential as well.     

A new insulin-mimetic vanadyl complex, (N-pyridylmethylaspartate)oxovanadium(IV) with VO(N2O2) coordination mode, and evaluation of its effect on uptake of D-glucose by Ehrlich ascites tumour cells

Because it has been confirmed that the vanadyl(IV) ion and its complexes act as insulin mimetics, a new organic vanadyl complex, (N-pyridylmethylaspartate)oxovanadium (VOPASP) with VO(N2O2) coordination mode, was prepared. Development of a simple and rapid in-vitro assay is needed for recognition of potent insulin-mimetic complexes. Treatment of Ehrlich ascites tumour cells with 2-deoxyglucose in the presence of vanadyl sulphate, or other vanadyl complexes with the same coordination mode (VOPASP, bis(picolinate)oxovanadium (VOPA) and bis(6-methyl picolinate)oxovanadium (VOMPA)), in the presence of 2-deoxy-D-[1-3H]glucose ([3H]deoxyglucose), resulted in concentration-dependent uptake of 2-deoxyglucose by the cells. The responses of the cells to the vanadyl complexes were reflected, in part, by results obtained from the free fatty acid-releasing assay using rat adipocytes. These results show that the in-vitro assay with Ehrlich ascites tumour cells provides an accurate and rapid assessment of glucose uptake by the cells. The assay is proposed as a means of predicting the insulin-mimetic activity of the vanadyl complexes and for studying the mechanism of action of the complexes.     

Pharmacokinetic study on gastrointestinal absorption of insulinomimetic vanadyl complexes in rats by ESR spectroscopy

Recently, we have shown that oral administrations of vanadyl (+4 oxidation state of vanadium) complexes normalize the blood glucose level of streptozotocin-induced diabetic rats (STZ-rats). To develop clinically useful insulin-mimetic vanadyl complexes, clarification of the pharmacokinetic features of vanadyl compounds is essential. First, we investigated the absorption processes of three compounds, an ionic form of vanadyl sulfate (VS) and the complex forms of bis(picolinato)oxovanadium(IV) (VO(pic)2) and bis(6-methylpicolinato)oxovanadium(IV) (VO(6mpa)2), from the gastrointestinal tract of healthy rats. The concentration curves of paramagnetic vanadyl species in the blood of rats after oral administration of these compounds, as monitored by X-band electron spin resonance (ESR) spectroscopy, exhibited biphasic increasing patterns, indicating that these compounds were absorbed from more than two sites in the gastrointestinal tract. The bioavailability of the compounds was enhanced in the following order on both oral and intraperitoneal administration: VO(6mpa)2 > VO(pic)2 > VS. In addition, bioavailability of the VO(6mpa)2 on ileal administration was enhanced compared with that using other administration sites such as the stomach and jejunum, and resulted in an enhancement about 1.8 fold that compared with oral administration. On the basis of these results, we concluded that the bioavailability of the complex is enhanced most effectively by delivery of the VO(6mpa)2 complex to the ileum.     

Bis(4,7-dimethyl and 5-dinitro-1,10-phenanthroline) sulfato-oxovanadium(IV)-mediated in vivo male germ cell apoptosis

Oxovanadium(IV) [VO] complexes of 1,10-phenanthroline are a new class of potent apoptosis-inducing cytotoxic agents against human testicular cancer cells in vitro. The present study investigated the in vivo ability of four(bis)-chelated 1,10-phenanthroline [phen] complexes of sulfato-oxovanadium(IV)-VO(phen)(2), VO(Cl-phen)(2), VO(Me(2)-phen)(2) and VO(NO(2)-phen)(2)-with and without substitutions, to induce testicular germ cell apoptosis. Male germ cell loss in mice was measured by determining the epididymal sperm count, testicular weight and histological evaluation of the testes. Repetitive intratesticular injection (7.5 mg kg(-1) testis(-1)) of bis-chelated 1,10-phenanthroline complexes of oxovanadium(IV) with 4,7-dimethyl [VO(Me(2)-phen)(2)] and 5-dinitro [VO(NO(2)-phen)(2)] substitution led to decreased sperm counts and reduced testicular weights. Histopathological examination of testicular sections from VO(Me(2)-phen)(2)- and VO(NO(2)-phen)(2)-treated mice revealed a marked inhibition of spermatogenesis and preferential loss of maturing, as well as elongated spermatids. In situ evaluation of seminiferous tubule cross-sections by terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick end-labeling (TUNEL) and laser scanning confocal microscopy showed characteristic apoptotic germ cells delineating the periphery of the seminiferous tubules. The ability of bis-chelated 4,7-dimethyl- and 5-dinitro-substituted 1,10-phenanthroline complexes of oxovanadium(IV) to induce germ cell apoptosis in vivo may have potential utility in the treatment of human testicular germ cell tumors.     

Improvement of hyperglycaemia and metabolic syndromes in type 2 diabetic KKAy mice by oral treatment with [meso-tetrakis(4-sulfonatophenyl) porphyrinato]oxovanadium(IV)(4-) complex

Recently, we reported that [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadium(IV)(4-), VO(tpps), shows in-vitro insulin-mimetic and in-vivo anti-diabetic activity in streptozotocin (STZ)-induced type 1 diabetic mice. This result prompted us to examine its ability in type 2 diabetic model KKA(y) mice with insulin resistance. We studied the in-vivo anti-diabetic activity of VO(tpps), compared with that of vanadium(IV) oxide sulfate, VS, as control. Both compounds were orally administered at doses of 5-10 mg (0.1-0.2 mmol) V/kg body weight to the KKA(y) mice for 28 days. VO(tpps) normalized the hyperglycaemia within 15 days, while VS lowered the blood glucose concentration only by a small degree. In addition, metabolic syndromes characterized by insulin and leptin resistance were significantly improved in VO(tpps)-treated KKA(y) mice compared with those treated with VS. The improvement in diabetes was validated by oral glucose tolerance test and decrease in HbA(1c) concentration. Based on these observations, VO(tpps) is proposed to be an orally active oxovanadium(IV)-porphyrin complex for treating not only type 2 diabetes but also metabolic syndromes in animals.     

Apoptosis-inducing oxovanadium(IV) complexes of 1,10-phenanthroline against human ovarian cancer

In a systematic effort to identify a potent anticancer agent against human ovarian cancer, we synthesized 15 oxovanadium(IV) complexes, and examined their cytotoxic activity against human ovarian cancer cell lines PA-1, SKOV-3, ES-2 and OVCAR-3 using a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyletetrazolium bromide]-based assay. The apoptosis-inducing ability of the oxovanadium compounds was evaluated by the two-color flow cytometric terminal deoxynucleotidyl transferase-based assay that labels 3'-hydroxyl ends of fragmented DNA (TUNEL) assay and confocal laser scanning microscopy. Notably, all eight oxovanadium complexes of 1,10 phenanthroline exhibited significant cytotoxicity and induced apoptosis within 24 h. The mono-chelated, VO(NO2-phen) and bis-chelated, VO(Me2-phen)2, VO(Cl-phen)2 and VO(NO2-phen)2 complexes were the most potent oxovanadium compounds, and killed target cancer cells at low micromolar concentrations. The marked differences in the cytotoxic activity of oxovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by the identity of the five-member bidentate ligands, as well as the nature of the substituents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apoptosis in human ovarian cancer cells. The lead compounds, VO(Me2-phen)2 and VO(NO2-phen)2, may be useful in the treatment of ovarian cancer.     

双(α-呋喃甲酸)氧钒的胰岛素样作用

钒作为人体必需的微量元素,在葡萄糖的代谢过程中起着重要作用.大量的体内外研究表明微量元素钒具有"胰岛素样(insulin-mimics)"作用,研究表明它能增加胰岛素的敏感性,是"胰岛素的促进剂(insulin-enhancing agent)",可用于治疗和缓解1型和2型糖尿病.     

Synthesis of oxovanadium(IV) Schiff base complexes derived from C-substituted diamines and pyridoxal-5-phosphate as antitumor agents

Oxovanadium (IV) complexes of N,N'-bispyridoxyl-5, 5'-bis (phosphate) ethylenediimine (L1) and N,N'-bis(pyridoxyl)-5,5'-bis(phosphate)-1'-(p-nitrobenzyl)ethylenediimine (L2) were synthesized by condensation of optically active C-substituted diamines and pyridoxal-5-phosphate. Oxovanadium (IV) complexes derived from L1 and L2 were evaluated as DNA cleavage agent (cleavage of supercoiled plasmid pBR322 DNA). Interestingly, both the oxovanadium (IV) complexes exhibited DNA nuclease activity, and the extent of oxidation of DNA by these vanadyl complexes was superior to VOSO(4) . The significant reduction in primary tumor and increased delay in tumor growth of 15 days was seen in the tumor regression analysis with oxovanadium (IV) complex of L1. With the preliminary studies performed with the pyridoxal-5-phosphate -based salen derivatives including the cytotoxicity and tumor regression, it is evident that the salen bifunctional chelating agent has obtained therapeutic potential if conjugated to a gene-specific targeting molecule for the oxidation of guanine residue.     

Royal Society of Chemistry--sixth international symposium on applied bioinorganic chemistry

This was the sixth in a series of symposia that began in Beijing, China in 1986. Approximately 100 chemists, environmental and biomedical scientists from 25 countries attended the meeting and presented some 80 papers on topics ranging from cancer chemotherapy to the production of paper. About half the papers presented could be broadly described as having medical implications, and of these, approximately half related directly to the use of platinum and the potential uses of other metals, such as palladium and the lanthanides, as anticancer agents. Many of these papers provided valuable insights into mechanisms of action and offered pointers for future research, but only rarely did they point to potential new drugs that might find early exploitation in clinical medicine. Two of the more exciting clinical developments were the introduction of the insulin-mimetic bis(maltolato)oxovanadium(IV) (KP-102; Kinetek Pharmaceuticals Inc/University of British Columbia) into clinical trials in the UK for the treatment of Type II diabetes, and the increasing importance of the orally active agent 3-hydroxy-pyridin-4-one-deferiprone (Apotex Inc/Cipla Ltd), in the treatment of iron overload in thalassemia.     

Metvan: a novel oxovanadium(IV) complex with broad spectrum anticancer activity

Among the 25 bis(cyclopentadienyl)vanadium(IV) and 14 oxovanadium(IV) compounds synthesised and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (metvan) was identified as the most promising multitargeted anticancer vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations, metvan induces apoptosis in human leukaemia cells, multiple myeloma cells and solid tumour cells derived from breast cancer, glioblastoma, ovarian, prostate and testicular cancer patients. It is highly effective against cisplatin-resistant ovarian cancer and testicular cancer cell lines. Metvan is much more effective than the standard chemotherapeutic agents dexamethasone and vincristine in inducing apoptosis in primary leukaemia cells from patients with acute lymphoblastic leukaemia, acute myeloid leukaemia or chronic acute myeloid leukaemia. Metvan-induced apoptosis is associated with a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species and depletion of glutathione. Treatment of leukaemia cells from acute lymphoblastic leukaemia, acute myeloid leukaemia and chronic acute myeloid leukaemia patients with metvan inhibits the constitutive expression as well as the gelatinolytic activities of matrix metalloproteinase-9 and -2. Treatment of human malignant glioblastoma and breast cancer cells with metvan at concentrations > 1 microM is associated with a nearly complete loss of the adhesive, migratory and invasive properties of the treated cancer cell populations. Metvan shows favourable pharmacokinetics in mice and does not cause acute or subacute toxicity at the dose levels tested (12.5 - 50 mg/kg). Therapeutic plasma concentrations > or = 5 microM, which are highly cytotoxic against human cancer cells, can be rapidly achieved and maintained in mice for at least 24 h after intraperitoneal bolus injection of a single 10 mg/kg non-toxic dose of metvan. Metvan exhibits significant antitumour activity, delays tumour progression and prolongs survival time in severe combined immunodeficient mouse xenograft models of human malignant glioblastoma and breast cancer. The broad spectrum anticancer activity of metvan together with favourable pharmacodynamic features and lack of toxicity warrants further development of this oxovanadium compound as a new anticancer agent. Metvan could represent the first vanadium complex as an alternative to platinum-based chemotherapy.     

双(α-呋喃甲酸)氧钒对胰岛素抵抗3T3-L1脂肪细胞糖摄取的影响

目的探讨新型的有机羧酸氧钒配合物双(α-呋喃甲酸)氧钒(BFOV)对正常及胰岛素抵抗的3T3-L1脂肪细胞糖摄取的影响。方法采用地塞米松诱导3T3-L1脂肪细胞建立胰岛素抵抗的细胞模型,研究双(α-呋喃甲酸)氧钒对正常及胰岛素抵抗3T3-L1脂肪细胞葡萄糖消耗的影响。结果双(α-呋喃甲酸)氧钒(2.5μmol·L-1~40μmol·L-1)对正常的3T3-L1脂肪细胞仅有增加葡萄糖消耗量的趋势,与空白对照组比较,差异无显著性;但能明显增加地塞米松诱导的胰岛素抵抗3T3-L1脂肪细胞的葡萄糖消耗量,改善模型细胞的胰岛素抵抗状态。结论双(α-呋喃甲酸)氧钒能促进胰岛素抵抗脂肪细胞的葡萄糖摄取,改善胰岛素抵抗状态。     

Synthesis and antifungal activity of oxovanadium(IV) complexes with Schiff bases

A series of preparations are reported representing complexes between a range of ligands [KHL = potassium salt of salicylidene-β-alanine, A¹ = 2,2′-bipyridylamine, A² = bis(benzylidene)ethylenediamine, A³ = thiophene-o-carboxaldene-aniline, A⁴ = thiophene-o-carboxaldene-p-toluidine, A⁵ = bis(benzylidene)-1,8-diaminonaphthalene, A⁶ = bis(acetophenone)ethylenediamine] and oxovanadium(IV) ion. Relevant electronic (UV), infrared (IR) spectra, thermogravimetric analyses, elemental analyses, and magnetic measurements are reported and interpreted in terms of the metal ion coordination geometry and, where appropriate, the likely octahedral structures of the compounds. The complexes are paramagnetic in nature. The antifungal activity of the complexes against A. niger, F. oxysporum, and A. flavus species is reported. All the tested complexes show higher antifungal activity as compared to free ligands, vanadyl sulfate, and the control (DMSO), but moderate activity as compared to the reference fungicides bavistin and emcarb. Published in Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 9, pp. 32–35, September, 2006.     

Antibacterial and antifungal oxovanadium(IV) complexes of triazole-derived Schiff bases

A newly synthesised series of antibacterial and antifungal triazole-derived Schiff base ligands (L ¹ )–(L ⁵ ) has been prepared by the condensation reaction of 3,5-diamino-1,2,4-triazole with methyl-, chloro- and nitro-substituted thiophene-2-carboxaldehydes in (1:2) molar ratio. The most probable structures of the synthesised Schiff base ligands were established on the basis of their physical, spectral (IR, ¹H and ¹³C NMR and mass spectrometry) and analytical (CHN analysis) data. These Schiff bases potentially act as bidentate ligand and were further made to react with the vanadyl(IV) sulphate (VOSO₄·5H₂O) in (1:2) (metal:ligand) molar ratio to prepare their oxovanadium(IV) complexes (1)–(5). All oxovanadium(IV) complexes showed a square-pyramidal geometry which was established on the basis of their physical, spectral and analytical data. The Schiff base ligands and their vanadyl(IV) complexes have been screened for their in vitro antibacterial, antifungal and brine shrimp bioassay. The antimicrobial activity data showed the vanadyl(IV) complexes to be more potent antibacterial and antifungal than the parent Schiff bases against one or more bacterial and fungal species.     

The long-term toxicity and hypoglycemic effect of vanadyl complexes on non-diabetic and type II diabetic mice

Vanadium compounds are promising anti-diabetic agents. However, the concern in the toxicity, especially the long-term renal side effectalong with diabetic status,is restricting the further development of this metal drug. Recently, we have prepared a bis((5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2-hydroxy-benzoatato) oxovanadium (BSOV), which exhibited excellent hypoglycemic effect with low acute toxicity. In order to facilitate the development of anti-diabetic vanadium complexes, especially BSOV, we studied the long-term toxicity and hypoglycemic effect of BSOV in comparison with bis(maltolato)oxovanadium (BMOV) on both non-diabetic and type II diabetic mice. The experiments confirmed a stable hypoglycemic effect for both the vanadium complexes over the testing period (6–7 months). However, the chronic administration of vanadium compounds slightly increased oxidative stress in ICR mice and the induced renal interstitial edema (RIE) in a part of the diabetic animals associated with low levels of serum albumin. The use of an antioxidant dietary supplement (a combination of vitamin C and Zinc gluconate) could prevent vanadium-induced oxidative stress but have marginal effect on RIE. However, BSOV caused much lower incidence of RIE than BMOV did, suggesting that BSOV is an important step towards the successful development of anti-diabetic vanadium drugs.     

Metallokinetic study of zinc in the blood of normal rats given insulinomimetic zinc(II) complexes and improvement of diabetes mellitus in type 2 diabetic GK rats by their oral administration

In order to understand the insulinomimetic activity of zinc(II) complexes, we studied the metallokinetic features of zinc in the blood of normal rats given the zinc complexes, bis(maltolato)zinc(II) (Zn(mal)(2)) and bis(6-methylpicolinato)zinc(II) (Zn(6mpa)(2)) by comparing each of them with an ionic form of zinc chloride (ZnCl(2)). The bioavailability of the zinc(II) complexes following oral administration was enhanced to 1.4-1.5-fold that of ZnCl(2) with respect to zinc level. Based on the results of a metallokinetic analysis and administration method in normal rats, we examined the antidiabetic ability of the zinc(II) complexes in GK rats, a model animal of type 2 diabetes mellitus. High blood glucose levels of GK rats were normalized following intraperitoneal injections and oral administration of the zinc(II) complexes, in which the Zn(6mpa)(2) complex was found to be more effective than Zn(mal)(2). The present results are noteworthy, not only due to their potential relevance for clinical application, but also for the development of new zinc(II) complexes.     

In vitro cytotoxic evaluation of novel dichlorodiorgano[<Emphasis Type="Italic">N</Emphasis>-(2-pyridylmethylene)arylamine]tin(IV) derivatives in human tumor cell lines

The present report overviews the studies on diorganotin(IV) complexes of N-(2-pyridylmethylene)arylamine, R₂SnCl₂.L (R = Me (1), Et (2), Bu (3) or Ph (4)) as cytotoxic agents. This family of complexes was designed to include highly electron-donating N^Nchelating ligand to afford octahedral R₂SnCl₂.L complexes of relatively high hydrolytic stability, with the aim to retain ligand binding throughout the biological activity for achieving controlled processes and allowing mechanistic evaluation. It is observed that the high cytotoxic activity is dependent on the Sn-R groups and Sn-N bond lengths, and which is related to the cytotoxic potential. Complex (2) was found to exhibit stronger cytotoxic activity in vitro particularly for A498 (renal cancer), IGROV (ovarian cancer), MCF-7 (breast cancer), and WIDR (colon cancer) of human tumour cell lines and the results are far superior to standard reference drugs e.g., doxorubicin, cisplatin, 5-fluorouracil, methotrexate, etoposide including paclitaxel. The important insights gained with the diorganotin(IV) compounds in regards to their cytotoxic activity are discussed.     

Cytostatic and antitumour properties of a new series of Pt (II) complexes with cyclopentylamine

Ten new Pt (II) complexes were synthesized and tested as potential antitumor drugs in vitro on KB human tumour cell line, and in vivo against four experimental tumour systems (P388, L1210, ADJ/PC6A and Yoshida sarcoma). The complexes contained two primary amine ligands (cyclopentylamine) with bidentate leaving ligands consisting of nitro-, dinitro- and sulfo-derivatives of phthalic and isophthalic anions. Various complexes showed a good cytostatic effect in vitro with ID50 from 0.29 and 0.99 mcg/ml. The Pt(cpa)2 (5-sulfo-IPA) appeared to be the most effective compound against P388 and L1210 (T/C% 310 and 250 respectively after three 50 mg/Kg i.p. injections) as well as against ADJ/PC6A (ID90 2.8 mg/kg after a single i.p. injection) and Yoshida sarcoma (T/C% 17.5 after a single 50 mg/kg i.p. injection), but the phthalic acid nitro-derivatives were also quite effective. As far as antileukemic effect was concerned, there was a fairly good correlation between the results in vitro and in vivo. Relationships between antitumour activity and pi electronic charge localization on O- atoms of leaving ligands (M.O. Huckel's Calculations) are also discussed.     

Bis(alpha-furancarboxylato)oxovanadium(IV) prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes

Previous studies showed that bis(alpha-furancarboxylato)oxovanadium(IV) (BFOV), an orally active anti-diabetic organic vanadium complex, could improve insulin resistance in animals with type 2 diabetes. The present study has been carried out to evaluate the effects of BFOV on insulin-resistant glucose metabolism using dexamethasone-treated 3T3-L1 adipocytes as an in-vitro model of insulin resistance. The results showed that BFOV, similar to vanadyl sulfate and rosiglitazone, caused a concentration-dependent increase in glucose consumption by insulin-resistant adipocytes. Moreover, BFOV enhanced the action of insulin and completely prevented the development of insulin resistance induced by dexamethasone, leading to glucose consumption equal to that by normal cells. In addition, dexamethasone reduced the mRNA expression of insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4) in 3T3-L1 adipocytes, while BFOV normalized the expression of IRS-1 and GLUT4. These findings suggest that BFOV prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes by enhancing expression of IRS-1 and GLUT4 mRNA.     

Anticancer platinum (IV) prodrugs with novel modes of activity

Over the past four decades, the search for improved platinum drugs based on the classical platinum (II)-diam(m)ine pharmacophore has yielded only a handful of successful candidates. New methodologies centred on platinum (IV) complexes, with better stability and expanded coordination spheres, offer the possibility of overcoming limitations inherent to platinum (II) drugs. In this review, novel strategies of targeting and killing cancer cells using platinum (IV) constructs are discussed. These approaches exploit the unique electrochemical characteristics and structural attributes of platinum (IV) complexes as a means of developing anticancer prodrugs that can target and selectively destroy cancer cells. Anticancer platinum (IV) prodrugs represent promising new strategies as targeted chemotherapeutic agents in the ongoing battle against cancer.     

Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents

Glucagon-like peptide-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPP IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, (iv) potency as insulin secretagogues, and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.