Terrigenous sediment-dominated reef platform infilling: an unexpected precursor to reef island formation and a test of the reef platform size–island age model in the Pacific

Low-lying coral reef islands are considered highly vulnerable to climate change, necessitating an improved understanding of when and why they form, and how the timing of formation varies within and among regions. Several testable models have been proposed that explain inter-regional variability as a function of sea-level history and, more recently, a reef platform size model has been proposed from the Maldives (central Indian Ocean) to explain intra-regional (intra-atoll) variability. Here we present chronostratigraphic data from Pipon Island, northern Great Barrier Reef (GBR), enabling us to test the applicability of existing regional island evolution models, and the platform size control hypothesis in a Pacific context. We show that reef platform infilling occurred rapidly (~4–5 mm yr⁻¹) under a “bucket-fill” type scenario. Unusually, this infilling was dominated by terrigenous sedimentation, with platform filling and subsequent reef flat formation complete by ~5000 calibrated years BP (cal BP). Reef flat exposure as sea levels slowly fell post highstand facilitated a shift towards intertidal and subaerial-dominated sedimentation. Our data suggest, however, a lag of ~1500 yr before island initiation (at ~3200 cal BP), i.e. later than that reported from smaller and more evolutionarily mature reef platforms in the region. Our data thus support: (1) the hypothesis that platform size acts to influence the timing of platform filling and subsequent island development at intra-regional scales; and (2) the hypothesis that the low wooded islands of the northern GBR conform to a model of island formation above an elevated reef flat under falling sea levels.

     

Structure and biological properties of first row d-transition metal complexes with N-substituted sulfonamides

Cobalt (II), copper (II), nickel (II) and zinc (II) complexes with 2-hydroxy-1-naphthaldehyde derived N-substituted sulfonamides have been synthesized and the nature of bonding and structure of compounds have been deduced from physical, analytical and spectral (IR, (1)H NMR, (13)C NMR, Mass and electronic) data. An octahedral geometry has been suggested for the complexes. Complexes along with the ligands were assessed for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi. The results revealed the ligands to possess moderate to significant antibacterial activity which was, in many cases, enhanced on chelation. Similar results were observed for antifungal activity. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.     

Carbonic anhydrase inhibitors. Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I, II and IX with some 1,3,4-oxadiazole- and 1,2,4-triazole-thiols

Novel mercapto-1,3,4-oxadiazole and -1,2,4-triazole derivatives were synthesized by various pathways starting from 4-(4-halogeno-phenylsulfonyl)benzoic acid hydrazides which were reacted with carbon disulfide or isothiocyanates. The heterocyclic mercaptans prepared in this way were assayed as inhibitors of three physiologically relevant isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), i.e., the cytosolic CA I and II, and the tumor-associated, transmembrane isozyme CA IX. Interesting biological activity was detected for some of the new mercaptans, with inhibition constants in the low micromolar range.     

Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies

The new antitumor sulfamate EMD 486019 was investigated for its interaction with twelve catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isozymes, hCA I – XIV. Similarly to 667-Coumate, a structurally related compound in phase II clinical trials as steroid sulfatase/CA inhibitor with potent antitumor properties, EMD 486019 acts as a strong inhibitor of isozymes CA II, VB, VII, IX, XII, and XIV (K_Is in the range of 13–19 nM) being less effective against other isozymes (K_Is in the range of 66–3600 nM against hCA I, IV, VA, VI, and mCA XIII, respectively). The complete inhibition profile of 667-Coumate against these mammalian CAs is also reported here for the first time. Comparing the X-ray crystal structures of the two adducts of CA II with EMD 486019 and 667-Coumate, distinct orientations of the bound sulfamates within the enzyme cavity were observed, which account for their distinct inhibition profiles. CA II/IX potent inhibitors belonging to the sulfamate class are thus valuable clinical candidates with potential for development as antitumor agents with a multifactorial mechanism of action.     

Carbonic anhydrase inhibitors: Inhibition of the new membrane-associated isoform XV with phenols

Inhibition of the newest isoform of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA XV, with a series of phenols was investigated. Murine CA XV showed an inhibition profile by phenols distinct of those of the cytosolic human isoforms CA I and II. Phenol and some of its 2-, 3-, and 4-substituted derivatives incorporating hydroxy, fluoro, carboxy, and acetamido moieties were effective CA XV inhibitors, with inhibition constants in the range of 7.20-11.30 microM, whereas compounds incorporating 4-amino-, 4-cyano, or 3-hydroxy groups were less effective (K(I)s of 335-434 microM). The best phenol inhibitor was clioquinol (K(I) of 2.33 microM). Phenols show a different inhibition mechanism as compared to sulfonamides and their isosteres, and may lead to the design of compounds with selectivity for inhibiting different CA isozymes with medicinal chemistry applications.     

Carbonic anhydrase inhibitors: inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid

Inhibition of 12 mammalian isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA I-XIV, with a series of phenols was investigated. The inhibition profile by phenols of these CAs was distinct from those of the sulfonamides and their isosteres, the main class of clinically used inhibitors. Phenol and some of its 2-, 3- and 4-substituted derivatives incorporating hydroxy-, fluoro-, carboxy-, amino-, cyano- and acetamido-moieties were generally effective low micromolar CA inhibitors, with inhibition constants in the range of 9.8-4003 microM against CA I, of 0.090-870 microM against CA II, of 0.71-885 microM against CA III, of 9.5-809 microM against CA IV, of 8.7-867 microM against CA VA, of 4.2-649 microM against CA VB, of 11.4-658 microM against CA VI, of 9.1-1359 microM against CA VII, of 8.8-517 microM against CA IX, of 4.1-598 microM against CA XII, of 12.2-697 microM against CA XIII and of 10.1-49.8 microM against CA XIV, respectively. The different mechanisms of inhibition by phenols as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest for the design of compounds with selectivity and/or specificity for some of the medicinal chemistry targets belonging to this enzyme family.     

Carbonic anhydrase activators: kinetic and X-ray crystallographic study for the interaction of D- and L-tryptophan with the mammalian isoforms I-XIV

An activation study of mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms I-XIV with D- and L-tryptophan has been performed both by means of kinetic and X-ray crystallographic techniques. These compounds show a time dependent activity against isozyme CA II, with activation constants of 1.13 microM for L-Trp and 0.37 microM for D-Trp, respectively, after 24 h of incubation between enzyme and activator. The high resolution X-ray crystal structure of the hCA II-D-Trp adduct revealed the activator to bind in a totally unprecedented way to the enzyme active site as compared to histamine, L-/D-Phe, L-/D-His or L-adrenaline. D-Trp is anchored at the edge of the CA II active site entrance, strongly interacting with amino acid residues Asp130, Phe131 and Gly132 as well as with a loop of a second symmetry related protein molecule from the asymmetric unit, by means of hydrogen bonds and several weak van der Waals interactions involving Glu234, Gly235, Glu236 and Glu238. Thus, a second activator binding site (B) within the CA II cavity has been detected, where only D-Trp was shown so far to bind, in addition to the activator binding site A, in which histamine, L-/D-Phe, and L-/D-His are bound. These findings explain the strong affinity of D-Trp for CA II and may be useful for designing novel classes of CA activators by using this compound as lead molecule.     

The proteoglycan region of the tumor-associated carbonic anhydrase isoform IX acts as anintrinsic buffer optimizing CO2 hydration at acidic pH values characteristic of solid tumors

The enzymatic activities of carbonic anhydrase (CA, EC 4.2.1.1) isozymes CA I, II, IX (catalytic domain (cdCA IX) and catalytic domain plus proteoglycan, flCA IX), XII and XIV were investigated as a function of pH for the CO₂ hydration to bicarbonate and a proton. The cytosolic isoforms CA I and II as well as the catalytic domain of CA IX, together with the transmembrane isoforms CA XII and XIV showed sigmoid pH dependencies of k_cat/K_M, with a pK_a of 6.90–7.10, showing thus optimal catalytic efficiency around pH 7. The full length CA IX had a similar shape of the pH dependency curve but with a pK_a of 6.49, having thus maximal catalytic activity at pH values around 6.5, typical of hypoxic solid tumors in which CA IX is overexpressed. The proteoglycan domain of CA IX (present only in this transmembrane isoform) may thus act as an intrinsic buffer promoting efficient CO₂ hydration at acidic pH values found in hypoxic tumors.     

Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active β-carbonic anhydrase from Mycobacterium tuberculosis,Rv3588c

The Rv3588c gene product of Mycobacterium tuberculosis, a β-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO₂ hydration (k_cat of 9.8 × 10⁵ s^?1, and k_cat/K_m of 9.3 × 10⁷ M^?1 s^?1) among the three β-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K_Is of 9–59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action.