A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desy... more A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner−Wadsworth−Emmons olefination, acid-catalyzed ketalization, Still−Gennari (Z)-selective olefination, and Dieckmann cyclization as key reactions.
153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patient... more 153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cation transporters known for transporting current platinum chemotherapies, IO-125 is also internalized via caveolin-mediated endocytic pathway, resulting in 10-20 fold greater uptake into cells as compared to oxaliplatin. Studies have implicated caveolin in TNBC progression and drug resistance, and harnessing this mechanism could confer enhanced activity. In animals bearing MDA-MB-231 xenografts, three cycles of IO-125 at well-tolerated doses (35 mg Pt/kg) resulted in significant tumor growth inhibition as compared to reported tumor inhibitions seen with existing platinum chemotherapies. Pharmacokinetic studies conducted in mice and rabbits indicate markedly improved profile of IO-125 as compared to oxaliplatin, showing a significantly higher area-under-the-curve (AUC), a substantial reduction in clearance and volume of distribution, with an enhanced half-life. Conclusions: Collectively, our findings demonstrate that IO-125 exhibits superior pharmacokinetics profile and biodistribution to tumors, resulting in enhanced anti-tumor activity in a TNBC xenograft model. Based on these observations, we propose that IO-125 may emerge as a potentially effective platinum-based drug for TNBC patients.
S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents... more S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in an oven/flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene and diethyl ether from Na and benzophenone; CH 2 Cl 2 , N-methyl pyrolidinone from CaH 2 ; MeOH, EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (60-120 mesh). Specific optical rotations [α] D are given in 10-1 degcm 2 g-1. Infrared spectra were recorded in CHCl 3 /neat (as mentioned) and reported in wave number (cm-1). 1 H and 13 C NMR chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-en-3-one (9). A mixture of furan 8 (60 mL, 82.5 mmol), 1, 2-dimethoxy ethane (90 mL) and Zn-Cu couple (10 g) was taken and cooled to −10 o C. To this mixture, a solution of 2, 4-dibromo-3-pentanone 7 (30 g, 122.99 mmol) in DME (50 mL) was added drop-wise over the period of 30 min. Further four portions of Zn-Cu couple (10 g each) were added at 30 min intervals. The reaction was stirred at the same temperature for additional 4 h. The metallic Zn-Cu couple was filtered and washed with hexane. Solvent was removed until the solution became turbid; at this stage water (50 mL) was added to the reaction mixture. The white precipitate of zinc hydroxide thus formed was filtered off and washed with ethyl acetate (4 x 25 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and removal of the solvent furnished 9 along with two isomeric ketones (15.33 g, 82%) as a light yellow liquid. Endo-3-hydroxy-endo,endo-2, 4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene (10). To a solution of ketones 9 (15.7 g, 103.16 mmol) in dichloromethane (100 mL), was added DIBAL-H (17.57 g, 20% solution in toluene, 12.4 mmol) at-10 o C over a period of 30 min. The reaction mixture was stirred for
153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patient... more 153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cat...
Triple-negative breast cancer (TNBC) is an aggressive form of cancer occurring in 15-20% of breas... more Triple-negative breast cancer (TNBC) is an aggressive form of cancer occurring in 15-20% of breast cancer patients, with most patients relapsing on currently approved therapy. Recent studies have shown activity of platinum chemotherapy in this class of patients. IO-125 is a novel platinum (II) chemotherapeutic agent with an unique coordination environment. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. The coordination environment in IO-125 facilitates supramolecular assembly and releases diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. In vitro cell viability studies using an array of breast cancer cell lines shows IO-125 exerts increased potency compared to carboplatin or oxaliplatin. The maximum tolerated (platinum-equivalent) dose (MTD) of IO-125 in mice was 8-fold higher than the MTD (platinum-equivalent) dose of oxaliplatin. The biodistribution and pharmacokinetic profile of IO-125 in plasma and tumor reve...
A study under field condition was carried out to evaluate physiological and biochemical propertie... more A study under field condition was carried out to evaluate physiological and biochemical properties of three cultivars of wax apple (Syzygium samarangense) namely ‘Jambu Madu Red’, ‘Masam Manis Pink’ and ‘Giant Green’. Physicochemical parameters, such as stomatal conductance, fruit development, pigmentation, fruit shape, yield, total soluble solids (TSS), titratable acidity (TA), sugar acid ratio, vitamin-C (vit-C), chlorophyll, carotene and anthocyanin content, in three cultivars of wax apple were investigated. The highest stomatal conductance, color development and yield were recorded in ‘Jambu Madu Red’ cultivar. Lowest amount of TA, highest TSS, sugar acid ratio and carotene content were also observed in this cultivar. Earlier color development, fruit maturity, good shape, highest vit-C and anthocyanin content were found in ‘Masam Manis Pink’. Meanwhile, the highest chlorophyll a, b and total chlorophyll (chlab) content and late maturation fruit were recorded in ‘Giant Green’ Cul...
Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targ... more Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targeted drug delivery. However, the synthesis of novel linkers for generating stable ADCs remains a key goal in the development of effective ADCs. Here we describe a unique linker (CORDLink) platform technology based on coordination chemistry that maintains the integrity of the antibody without impacting binding to the target. Using an anti-HER2 monoclonal antibody and camptothecin, as examples of the targeting antibody and a highly cytotoxic payload respectively, we demonstrate that the linker enables the formation of a stable ADC via supramolecular coordinate bond. The robustness of our process and consistency was characterized through a variety of analytical tools, such as SE-HPLC, CEX-HPLC and HI-HPLC, while peptide mapping was done to elucidate the exact site of attachment. The ADCs were found to remain intact in media and serum using a fluorescence-based RP-HPLC method. The anti-HER2 ...
Despite the widespread use of platinum chemotherapy, only few drugs have been approved in this cl... more Despite the widespread use of platinum chemotherapy, only few drugs have been approved in this class of molecules. Here, we describe a novel supramolecular chemistry-based platform technology to engineer more potent oxaliplatin analogues. In IO125, a unique platinum (II) is tethered to a cholesterol backbone via a monocarboxylato bond and an N→Pt coordination environment, releasing diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. The molecule facilitates assembly into defined nanoscale supramolecular structures of uniform size distribution as measured using dynamic light scatter and electron microscopy. Such a supramolecular therapeutic demonstrates enhanced activity compared with oxaliplatin in 4T1 and MDA-MB-231 triple negative breast cancer lines. The uptake of IO125-based supramolecular therapeutic was 10-20 fold greater than free oxaliplatin in these cells. In addition, the nanoparticles exhibited significantly lower IC50 values in comparison to oxaliplati...
This study represents the first paper of the effects of growth regulators on the physiochemical a... more This study represents the first paper of the effects of growth regulators on the physiochemical and phytochemical properties of the wax apple fruit, a widely cultivated fruit tree in southeast Asia. Net photosynthesis, sucrose phosphate synthase (SPS) activity, peel color, fruit firmness, juice content, pH value, total soluble solids (TSSs), and the sugar acid ratio were all significantly increased in growth regulators (PGRs) treated fruits. The application of gibberellin (GA3), naphthalene acetic acid (NAA), and 2,4-dichlorophenoxy acetic acid (2,4-D) significantly reduced titratable acidity and increased total sugar and carbohydrate content compared to the control. The 50 mg/L GA3, 10 mg/L NAA, and 5 mg/L 2,4-D treatments produced the greatest increases in phenol and flavonoid content; vitamin C content was also higher for these treatments. PGR treatment significantly affected chlorophyll, anthocyanin, and carotene content and produced higher phenylalanine ammonia lyase (PAL) and ...
We have achieved the synthesis of C15–C27 fragment of venturicidine X using desymmetrization prot... more We have achieved the synthesis of C15–C27 fragment of venturicidine X using desymmetrization protocol, substrate-controlled Grignard reaction, Barton–McCombie reaction, Sharpless epoxidation, and TBSOTf-mediated rearrangement to produce the aldol product through a non-aldol route as the key step following 23 longest linear sequences with 6.4% overall yield starting from a known intermediate 11.
S o l v e n t-F r e e C o u p l i n g o f D i a z o C o m p o u n d s w i t h A z a a r o m a t i... more S o l v e n t-F r e e C o u p l i n g o f D i a z o C o m p o u n d s w i t h A z a a r o m a t i c s
SummaryWag31 of Mycobacterium tuberculosis belongs to the DivIVA family of proteins known to regu... more SummaryWag31 of Mycobacterium tuberculosis belongs to the DivIVA family of proteins known to regulate cell morphology in Gram‐positive bacteria. Here we demonstrate an unrecognized, novel role of Wag31 in oxidatively stressed mycobacteria. We report the cleavage of penicillin‐binding protein 3 (PBP3) by the intramembrane metalloprotease Rv2869c (MSMEG_2579) in oxidatively stressed cells. Amino acids 102A and 103A of PBP3 are required for Rv2869c‐mediated cleavage. Wag31MTB, by virtue of its interaction with PBP3 through amino acid residues 46NSD48, protects it from oxidative stress‐induced cleavage. PBP3 undergoes cleavage in Mycobacterium smegmatis (strain PM2) harbouring wag31(Δ46NSD48) instead of the wild type, with concomitant reduction in ability to withstand oxidative stress. Overexpression of Wag31(Δ46NSD48) attenuates the survival of M. tuberculosis in macrophages with concomitant cleavage of PBP3, and renders the organism more susceptible towards hydrogen peroxide as well a...
S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents... more S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in an oven/flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene and diethyl ether from Na and benzophenone; CH 2 Cl 2 , N-methyl pyrolidinone from CaH 2 ; MeOH, EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (60-120 mesh). Specific optical rotations [α] D are given in 10-1 degcm 2 g-1. Infrared spectra were recorded in CHCl 3 /neat (as mentioned) and reported in wave number (cm-1). 1 H and 13 C NMR chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-en-3-one (9). A mixture of furan 8 (60 mL, 82.5 mmol), 1, 2-dimethoxy ethane (90 mL) and Zn-Cu couple (10 g) was taken and cooled to −10 o C. To this mixture, a solution of 2, 4-dibromo-3-pentanone 7 (30 g, 122.99 mmol) in DME (50 mL) was added drop-wise over the period of 30 min. Further four portions of Zn-Cu couple (10 g each) were added at 30 min intervals. The reaction was stirred at the same temperature for additional 4 h. The metallic Zn-Cu couple was filtered and washed with hexane. Solvent was removed until the solution became turbid; at this stage water (50 mL) was added to the reaction mixture. The white precipitate of zinc hydroxide thus formed was filtered off and washed with ethyl acetate (4 x 25 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and removal of the solvent furnished 9 along with two isomeric ketones (15.33 g, 82%) as a light yellow liquid. Endo-3-hydroxy-endo,endo-2, 4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene (10). To a solution of ketones 9 (15.7 g, 103.16 mmol) in dichloromethane (100 mL), was added DIBAL-H (17.57 g, 20% solution in toluene, 12.4 mmol) at-10 o C over a period of 30 min. The reaction mixture was stirred for
A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desy... more A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner−Wadsworth−Emmons olefination, acid-catalyzed ketalization, Still−Gennari (Z)-selective olefination, and Dieckmann cyclization as key reactions.
A study was carried out to investigate the effects of different girdling techniques on the growth... more A study was carried out to investigate the effects of different girdling techniques on the growth, development and quality of red wax apple fruits (Syzygium samarangense). Selected horticultural parameters were monitored at one week interval during the growth period from December 2008 to October 2010, using I, C, V shaped, 50%, and 100% girdling. Girdling was applied 2 weeks before flowering. The results showed that the C-shaped girdling technique produced the best results with regard to the fruit setting and chlorophyll ...
To cite this paper: Khandaker, MM, AS Hossain, N. Osman and AN Boyce, 2011. Application of girdli... more To cite this paper: Khandaker, MM, AS Hossain, N. Osman and AN Boyce, 2011. Application of girdling for improved fruit retention, yield and fruit quality in Syzygium samarangense under field conditions. Int. J. Agric. Biol., 13: 1824 ... Application of Girdling for Improved Fruit ...
Pt(ii)-based linkers re-bridge the antibody chainsviastrong Pt–S interaction thereby imparting ho... more Pt(ii)-based linkers re-bridge the antibody chainsviastrong Pt–S interaction thereby imparting homogeneity, site-specificity and stability to the antibody–drug conjugate.
A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desy... more A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner−Wadsworth−Emmons olefination, acid-catalyzed ketalization, Still−Gennari (Z)-selective olefination, and Dieckmann cyclization as key reactions.
153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patient... more 153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cation transporters known for transporting current platinum chemotherapies, IO-125 is also internalized via caveolin-mediated endocytic pathway, resulting in 10-20 fold greater uptake into cells as compared to oxaliplatin. Studies have implicated caveolin in TNBC progression and drug resistance, and harnessing this mechanism could confer enhanced activity. In animals bearing MDA-MB-231 xenografts, three cycles of IO-125 at well-tolerated doses (35 mg Pt/kg) resulted in significant tumor growth inhibition as compared to reported tumor inhibitions seen with existing platinum chemotherapies. Pharmacokinetic studies conducted in mice and rabbits indicate markedly improved profile of IO-125 as compared to oxaliplatin, showing a significantly higher area-under-the-curve (AUC), a substantial reduction in clearance and volume of distribution, with an enhanced half-life. Conclusions: Collectively, our findings demonstrate that IO-125 exhibits superior pharmacokinetics profile and biodistribution to tumors, resulting in enhanced anti-tumor activity in a TNBC xenograft model. Based on these observations, we propose that IO-125 may emerge as a potentially effective platinum-based drug for TNBC patients.
S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents... more S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in an oven/flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene and diethyl ether from Na and benzophenone; CH 2 Cl 2 , N-methyl pyrolidinone from CaH 2 ; MeOH, EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (60-120 mesh). Specific optical rotations [α] D are given in 10-1 degcm 2 g-1. Infrared spectra were recorded in CHCl 3 /neat (as mentioned) and reported in wave number (cm-1). 1 H and 13 C NMR chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-en-3-one (9). A mixture of furan 8 (60 mL, 82.5 mmol), 1, 2-dimethoxy ethane (90 mL) and Zn-Cu couple (10 g) was taken and cooled to −10 o C. To this mixture, a solution of 2, 4-dibromo-3-pentanone 7 (30 g, 122.99 mmol) in DME (50 mL) was added drop-wise over the period of 30 min. Further four portions of Zn-Cu couple (10 g each) were added at 30 min intervals. The reaction was stirred at the same temperature for additional 4 h. The metallic Zn-Cu couple was filtered and washed with hexane. Solvent was removed until the solution became turbid; at this stage water (50 mL) was added to the reaction mixture. The white precipitate of zinc hydroxide thus formed was filtered off and washed with ethyl acetate (4 x 25 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and removal of the solvent furnished 9 along with two isomeric ketones (15.33 g, 82%) as a light yellow liquid. Endo-3-hydroxy-endo,endo-2, 4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene (10). To a solution of ketones 9 (15.7 g, 103.16 mmol) in dichloromethane (100 mL), was added DIBAL-H (17.57 g, 20% solution in toluene, 12.4 mmol) at-10 o C over a period of 30 min. The reaction mixture was stirred for
153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patient... more 153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cat...
Triple-negative breast cancer (TNBC) is an aggressive form of cancer occurring in 15-20% of breas... more Triple-negative breast cancer (TNBC) is an aggressive form of cancer occurring in 15-20% of breast cancer patients, with most patients relapsing on currently approved therapy. Recent studies have shown activity of platinum chemotherapy in this class of patients. IO-125 is a novel platinum (II) chemotherapeutic agent with an unique coordination environment. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. The coordination environment in IO-125 facilitates supramolecular assembly and releases diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. In vitro cell viability studies using an array of breast cancer cell lines shows IO-125 exerts increased potency compared to carboplatin or oxaliplatin. The maximum tolerated (platinum-equivalent) dose (MTD) of IO-125 in mice was 8-fold higher than the MTD (platinum-equivalent) dose of oxaliplatin. The biodistribution and pharmacokinetic profile of IO-125 in plasma and tumor reve...
A study under field condition was carried out to evaluate physiological and biochemical propertie... more A study under field condition was carried out to evaluate physiological and biochemical properties of three cultivars of wax apple (Syzygium samarangense) namely ‘Jambu Madu Red’, ‘Masam Manis Pink’ and ‘Giant Green’. Physicochemical parameters, such as stomatal conductance, fruit development, pigmentation, fruit shape, yield, total soluble solids (TSS), titratable acidity (TA), sugar acid ratio, vitamin-C (vit-C), chlorophyll, carotene and anthocyanin content, in three cultivars of wax apple were investigated. The highest stomatal conductance, color development and yield were recorded in ‘Jambu Madu Red’ cultivar. Lowest amount of TA, highest TSS, sugar acid ratio and carotene content were also observed in this cultivar. Earlier color development, fruit maturity, good shape, highest vit-C and anthocyanin content were found in ‘Masam Manis Pink’. Meanwhile, the highest chlorophyll a, b and total chlorophyll (chlab) content and late maturation fruit were recorded in ‘Giant Green’ Cul...
Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targ... more Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targeted drug delivery. However, the synthesis of novel linkers for generating stable ADCs remains a key goal in the development of effective ADCs. Here we describe a unique linker (CORDLink) platform technology based on coordination chemistry that maintains the integrity of the antibody without impacting binding to the target. Using an anti-HER2 monoclonal antibody and camptothecin, as examples of the targeting antibody and a highly cytotoxic payload respectively, we demonstrate that the linker enables the formation of a stable ADC via supramolecular coordinate bond. The robustness of our process and consistency was characterized through a variety of analytical tools, such as SE-HPLC, CEX-HPLC and HI-HPLC, while peptide mapping was done to elucidate the exact site of attachment. The ADCs were found to remain intact in media and serum using a fluorescence-based RP-HPLC method. The anti-HER2 ...
Despite the widespread use of platinum chemotherapy, only few drugs have been approved in this cl... more Despite the widespread use of platinum chemotherapy, only few drugs have been approved in this class of molecules. Here, we describe a novel supramolecular chemistry-based platform technology to engineer more potent oxaliplatin analogues. In IO125, a unique platinum (II) is tethered to a cholesterol backbone via a monocarboxylato bond and an N→Pt coordination environment, releasing diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. The molecule facilitates assembly into defined nanoscale supramolecular structures of uniform size distribution as measured using dynamic light scatter and electron microscopy. Such a supramolecular therapeutic demonstrates enhanced activity compared with oxaliplatin in 4T1 and MDA-MB-231 triple negative breast cancer lines. The uptake of IO125-based supramolecular therapeutic was 10-20 fold greater than free oxaliplatin in these cells. In addition, the nanoparticles exhibited significantly lower IC50 values in comparison to oxaliplati...
This study represents the first paper of the effects of growth regulators on the physiochemical a... more This study represents the first paper of the effects of growth regulators on the physiochemical and phytochemical properties of the wax apple fruit, a widely cultivated fruit tree in southeast Asia. Net photosynthesis, sucrose phosphate synthase (SPS) activity, peel color, fruit firmness, juice content, pH value, total soluble solids (TSSs), and the sugar acid ratio were all significantly increased in growth regulators (PGRs) treated fruits. The application of gibberellin (GA3), naphthalene acetic acid (NAA), and 2,4-dichlorophenoxy acetic acid (2,4-D) significantly reduced titratable acidity and increased total sugar and carbohydrate content compared to the control. The 50 mg/L GA3, 10 mg/L NAA, and 5 mg/L 2,4-D treatments produced the greatest increases in phenol and flavonoid content; vitamin C content was also higher for these treatments. PGR treatment significantly affected chlorophyll, anthocyanin, and carotene content and produced higher phenylalanine ammonia lyase (PAL) and ...
We have achieved the synthesis of C15–C27 fragment of venturicidine X using desymmetrization prot... more We have achieved the synthesis of C15–C27 fragment of venturicidine X using desymmetrization protocol, substrate-controlled Grignard reaction, Barton–McCombie reaction, Sharpless epoxidation, and TBSOTf-mediated rearrangement to produce the aldol product through a non-aldol route as the key step following 23 longest linear sequences with 6.4% overall yield starting from a known intermediate 11.
S o l v e n t-F r e e C o u p l i n g o f D i a z o C o m p o u n d s w i t h A z a a r o m a t i... more S o l v e n t-F r e e C o u p l i n g o f D i a z o C o m p o u n d s w i t h A z a a r o m a t i c s
SummaryWag31 of Mycobacterium tuberculosis belongs to the DivIVA family of proteins known to regu... more SummaryWag31 of Mycobacterium tuberculosis belongs to the DivIVA family of proteins known to regulate cell morphology in Gram‐positive bacteria. Here we demonstrate an unrecognized, novel role of Wag31 in oxidatively stressed mycobacteria. We report the cleavage of penicillin‐binding protein 3 (PBP3) by the intramembrane metalloprotease Rv2869c (MSMEG_2579) in oxidatively stressed cells. Amino acids 102A and 103A of PBP3 are required for Rv2869c‐mediated cleavage. Wag31MTB, by virtue of its interaction with PBP3 through amino acid residues 46NSD48, protects it from oxidative stress‐induced cleavage. PBP3 undergoes cleavage in Mycobacterium smegmatis (strain PM2) harbouring wag31(Δ46NSD48) instead of the wild type, with concomitant reduction in ability to withstand oxidative stress. Overexpression of Wag31(Δ46NSD48) attenuates the survival of M. tuberculosis in macrophages with concomitant cleavage of PBP3, and renders the organism more susceptible towards hydrogen peroxide as well a...
S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents... more S4 General method: Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in an oven/flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene and diethyl ether from Na and benzophenone; CH 2 Cl 2 , N-methyl pyrolidinone from CaH 2 ; MeOH, EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using Spectrochem silica gel (60-120 mesh). Specific optical rotations [α] D are given in 10-1 degcm 2 g-1. Infrared spectra were recorded in CHCl 3 /neat (as mentioned) and reported in wave number (cm-1). 1 H and 13 C NMR chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Endo,endo-2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-en-3-one (9). A mixture of furan 8 (60 mL, 82.5 mmol), 1, 2-dimethoxy ethane (90 mL) and Zn-Cu couple (10 g) was taken and cooled to −10 o C. To this mixture, a solution of 2, 4-dibromo-3-pentanone 7 (30 g, 122.99 mmol) in DME (50 mL) was added drop-wise over the period of 30 min. Further four portions of Zn-Cu couple (10 g each) were added at 30 min intervals. The reaction was stirred at the same temperature for additional 4 h. The metallic Zn-Cu couple was filtered and washed with hexane. Solvent was removed until the solution became turbid; at this stage water (50 mL) was added to the reaction mixture. The white precipitate of zinc hydroxide thus formed was filtered off and washed with ethyl acetate (4 x 25 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and removal of the solvent furnished 9 along with two isomeric ketones (15.33 g, 82%) as a light yellow liquid. Endo-3-hydroxy-endo,endo-2, 4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene (10). To a solution of ketones 9 (15.7 g, 103.16 mmol) in dichloromethane (100 mL), was added DIBAL-H (17.57 g, 20% solution in toluene, 12.4 mmol) at-10 o C over a period of 30 min. The reaction mixture was stirred for
A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desy... more A highly stereoselective total synthesis of (−)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner−Wadsworth−Emmons olefination, acid-catalyzed ketalization, Still−Gennari (Z)-selective olefination, and Dieckmann cyclization as key reactions.
A study was carried out to investigate the effects of different girdling techniques on the growth... more A study was carried out to investigate the effects of different girdling techniques on the growth, development and quality of red wax apple fruits (Syzygium samarangense). Selected horticultural parameters were monitored at one week interval during the growth period from December 2008 to October 2010, using I, C, V shaped, 50%, and 100% girdling. Girdling was applied 2 weeks before flowering. The results showed that the C-shaped girdling technique produced the best results with regard to the fruit setting and chlorophyll ...
To cite this paper: Khandaker, MM, AS Hossain, N. Osman and AN Boyce, 2011. Application of girdli... more To cite this paper: Khandaker, MM, AS Hossain, N. Osman and AN Boyce, 2011. Application of girdling for improved fruit retention, yield and fruit quality in Syzygium samarangense under field conditions. Int. J. Agric. Biol., 13: 1824 ... Application of Girdling for Improved Fruit ...
Pt(ii)-based linkers re-bridge the antibody chainsviastrong Pt–S interaction thereby imparting ho... more Pt(ii)-based linkers re-bridge the antibody chainsviastrong Pt–S interaction thereby imparting homogeneity, site-specificity and stability to the antibody–drug conjugate.
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