Primena PAMPA tehnike i QSPR analize u proceni gastrointestinalne apsorpcije i dizajniranju novih biološki aktivnih jedinjenja

Abstract

PAMPA (Parallel Artificial Membrane Permeability Assay) je brza i jednostavna in vitro tehnika za procenu gastrointestinalne apsorpcije. Zasniva se na pasivnoj difuziji ispitivanih supstanci kroz veštačku membranu koja simulira gastrointestinalni trakt. QSPR (Quantitative Structure‐ Permeability Relationship Analysis) povezuje rezultate PAMPA testa sa fizičko‐hemijskim osobinama ispitivanih jedinjenja, na osnovu čega je moguć dizajn novih derivata sa poboljšanom apsorpcijom. Cilj rada je procena gastrointestinalne apsorpcije trinaest β‐hidroksi‐β‐arilalkanskih kiselina sa antiinflamatornom aktivnošću i četrnaest derivata 1,2‐etandiamina i 1,3‐ propandiamina sa antiproliferativnom aktivnošću primenom PAMPA testa, kao i dizajn novih jedinjenja na osnovu QSPR analiza. Gastrointestinalna apsorpcija je procenjena na hidrofobnim PVDF PAMPA pločama, impregniranim 1% rastvorom lecitina jajeta u dodekanu (w/v). Molekulski deskriptori ispitivanih jedinjenja su izračunati u programu Dragon i pomoću platforme ChemDes. QSPR modeli su napravljeni u programima Simca 12+ P i STATISTICA. Za sva ispitivana jedinjenja određeni su koeficijenti permeabilnosti (Papp) primenom PAMPA testa, a za formiranje QSPR modela izračunati su i negativni logaritmi ovih koeficijenata (‐logP app). Izdvojene su β‐hidroksi‐β‐arilalkanske kiseline (1C, 1B i 2C), kao i derivati 1,2‐etandiamina i 1,3‐propandiamina (DM‐EDCP, EDCP i DM‐PDCP) sa najvećom permeabilnošću kroz PAMPA membranu. Formirani su ANN‐, MLR‐, PLS‐ i SVM‐QSPR modeli, pri čemu su najpouzdaniji modeli za predviđanje permeabilnosti MLR(‐logP app) (za β‐hidroksi‐β‐arilalkanske kiseline), odnosno PLS(‐logP app) (za derivate 1,2‐etandiamina i 1,3‐propandiamina). Na osnovu deskriptora koji formiraju izdvojene modele predložene su strukturne promene koje bi trebalo da poboljšaju permeabilnost kroz PAMPA veštačku membranu i gastrointestinalnu apsorpciju. Primenom PAMPA tehnike procenjena je gastrointestinalna apsorpcija trinaest β‐hidroksi‐β‐arilalkanskih kiselina, kao i četrnaest derivata 1,2‐etandiamina i 1,3‐ propandiamina. Izdvojeni su derivati sa najvećom permeabilnošću i formirani su QSPR modeli. Analizom najpouzdanijih modela, predložene su strukturne promene i dizajnirani su novi derivati od kojih se može očekivati bolja gastrointestinalna apsorpcija.

PAMPA (Parallel Artificial Membrane Permeability Assay) is a fast and simple in vitro technique used for the evaluation of gastrointestinal absorption. It is based on passive diffusion of tested substances through artificial membrane which simulates gastrointestinal tract. QSPR (Quantitative Structure‐Permeability Relationship Analysis) relates PAMPA results to physico‐chemical properties of tested compounds, which can be used for design of new derivatives with improved absorption. The aim of this work was evaluation of gastrointestinal absorption of thirteen β‐hydroxy‐β‐ arylalkanoic acids with antiinflammatory activity and fourteen derivatives of 1,2‐ ethanediamine and 1,3‐propanediamine with antiproliferative activity using PAMPA, as well as design of novel derivatives on the basis of QSPR analyses. Gastrointestinal absorption was evaluated using hydrophobic PAMPA plates impregnated with 1% egg lecithin solution in dodecane (w/v). Molecular descriptors of tested compounds were calculated using Dragon software and ChemDes platform. QSPR models were created in Simca 12+P and STATISTICA programs. Permeability coefficients (Papp) of all tested compounds were determined using PAMPA, whereas for QSPR modelling negative logarithms of these coefficients (‐logPapp) were calculated. β‐hydroxy‐β‐arylalkanoic acids (1C, 1B and 2C), as well as derivatives of 1,2‐ethanediamine and 1,3‐propanediamine (DM‐EDCP, EDCP and DM‐PDCP) with the highest PAMPA permeability were underlined. ANN‐, MLR‐, PLS‐ and SVM‐QSPR models were created, and the most reliable for permeability prediction were MLR(‐ logPapp) (β‐hydroxy‐β‐arylalkanoic acids) and PLS(‐logPapp) (derivatives of 1,2‐ ethanediamine and 1,3‐propanediamine). On the basis of descriptors that form selected models, structural modifications that should improve PAMPA permeability and gastrointestinal absorption were proposed. Gastrointestinal absorption of thirteen β‐hydroxy‐β‐arylalkanoic acids and fourteen derivatives of 1,2‐ethanediamine and 1,3‐propanediamine was evaluated using PAMPA technique. Derivatives with the highest permeability were underlined and QSPR models were created. After the analysis of the most reliable models, structural modifications were proposed and new derivatives with better expected gastrointestinal absorption were designed.